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Fulltext Sphingosine Kinase 1 Signaling in Breast Cancer: A Potential Target to Tackle Breast Cancer Stem Cells

Hii LW, Chung FF, Mai CW, Ng PY, Leong CO

Front Mol Biosci, 2021;8:748470.
PMID: 34820423 DOI: 10.3389/fmolb.2021.748470

Sphingosine kinases (SPHKs) are conserved lipid enzymes that catalyze the formation of sphingosine-1-phosphate (S1P) through ATP-dependent phosphorylation of sphingosine. Two distinct SPHK isoforms, namely SPHK1 and SPHK2, have been identified to date, and the former has been implicated for its oncogenic roles in cancer development and progression. While SPHK1 signaling axis has been extensively studied in non-stem breast cancer cells, recent evidence has emerged to suggest a role of SPHK1 in regulating cancer stem cells (CSCs). With the clinical implications of CSCs in disease relapse and metastasis, it is believed that therapeutic approaches that can eradicate both non-stem cancer cells and CSCs could be a key to cancer cure. In this review, we first explore the oncogenic functions of sphingosine kinase 1 in human cancers and summarize current research findings of SPHK1 signaling with a focus on breast cancer. We also discuss the therapeutic potentials and perspectives of targeting SPHK1 signaling in breast cancer and cancer stem cells. We aim to offer new insights and inspire future studies looking further into the regulatory functions of SPHK1 in CSC-driven tumorigenesis, uncovering novel therapeutic avenues of using SPHK1-targeted therapy in the treatment of CSC-enriched refractory cancers.
Fulltext Roles of Inflammasomes in Epstein-Barr Virus-Associated Nasopharyngeal Cancer

Looi CK, Hii LW, Chung FF, Mai CW, Lim WM, Leong CO

Cancers (Basel), 2021 Apr 08;13(8).
PMID: 33918087 DOI: 10.3390/cancers13081786

Epstein-Barr virus (EBV) infection is recognised as one of the causative agents in most nasopharyngeal carcinoma (NPC) cases. Expression of EBV viral antigens can induce host's antiviral immune response by activating the inflammasomes to produce pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and IL-18. These cytokines are known to be detrimental to a wide range of virus-infected cells, in which they can activate an inflammatory cell death program, called pyroptosis. However, aberrant inflammasome activation and production of its downstream cytokines lead to chronic inflammation that may contribute to various diseases, including NPC. In this review, we summarise the roles of inflammasomes during viral infection, how EBV evades inflammasome-mediated immune response, and progress into tumourigenesis. The contrasting roles of inflammasomes in cancer, as well as the current therapeutic approaches used in targeting inflammasomes, are also discussed in this review. While the inflammasomes appear to have dual roles in carcinogenesis, there are still many questions that remain unanswered. In particular, the exact molecular mechanism responsible for the regulation of the inflammasomes during carcinogenesis of EBV-associated NPC has not been explored thoroughly. Furthermore, the current practical application of inflammasome inhibitors is limited to specific tumour types, hence, further studies are warranted to discover the potential of targeting the inflammasomes for the treatment of NPC.
Histone deacetylase (HDAC) inhibitors and doxorubicin combinations target both breast cancer stem cells and non-stem breast cancer cells simultaneously

Hii LW, Chung FF, Soo JS, Tan BS, Mai CW, Leong CO

Breast Cancer Res Treat, 2020 Feb;179(3):615-629.
PMID: 31784862 DOI: 10.1007/s10549-019-05504-5

PURPOSE: Breast cancer stem cells (CSCs) are a small subpopulation of cancer cells that have high capability for self-renewal, differentiation, and tumor initiation. CSCs are resistant to chemotherapy and radiotherapy, and are responsible for cancer recurrence and metastasis.
METHODS: By utilizing a panel of breast cancer cells and mammospheres culture as cell-based screening platforms, we performed high-throughput chemical library screens to identify agents that are effective against breast CSCs and non-CSCs. The hit molecules were paired with conventional chemotherapy to evaluate the combinatorial treatment effects on breast CSCs and non-CSCs.
RESULTS: We identified a total of 193 inhibitors that effectively targeting both breast CSCs and non-CSCs. We observed that histone deacetylase inhibitors (HDACi) synergized conventional chemotherapeutic agents (i.e., doxorubicin and cisplatin) in targeting breast CSCs and non-CSCs simultaneously. Further analyses revealed that quisinostat, a potent inhibitor for class I and II HDACs, potentiated doxorubicin-induced cytotoxicity in both breast CSCs and non-CSCs derived from the basal-like (MDA-MB-468 and HCC38), mesenchymal-like (MDA-MB-231), and luminal-like breast cancer (MCF-7). It was also observed that the basal-like breast CSCs and non-CSCs were more sensitive to the co-treatment of quisinostat with doxorubicin compared to that of the luminal-like breast cancer subtype.
CONCLUSION: In conclusion, this study demonstrates the potential of HDACi as therapeutic options, either as monotherapy or in combination with chemotherapeutics against refractory breast cancer.
Fulltext The synergism of Clinacanthus nutans Lindau extracts with gemcitabine: downregulation of anti-apoptotic markers in squamous pancreatic ductal adenocarcinoma

Hii LW, Lim SE, Leong CO, Chin SY, Tan NP, Lai KS, et al.

BMC Complement Altern Med, 2019 Sep 14;19(1):257.
PMID: 31521140 DOI: 10.1186/s12906-019-2663-9

BACKGROUND: Clinacanthus nutans extracts have been consumed by the cancer patients with the hope that the extracts can kill cancers more effectively than conventional chemotherapies. Our previous study reported its anti-inflammatory effects were caused by inhibiting Toll-like Receptor-4 (TLR-4) activation. However, we are unsure of its anticancer effect, and its interaction with existing chemotherapy.
METHODS: We investigated the anti-proliferative efficacy of polar leaf extracts (LP), non-polar leaf extracts (LN), polar stem extract (SP) and non-polar stem extracts (SN) in human breast, colorectal, lung, endometrial, nasopharyngeal, and pancreatic cancer cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT assay. The most potent extracts was tested along with gemcitabine using our established drug combination analysis. The effect of the combinatory treatment in apoptosis were quantified using enzyme-linked immunosorbent assay (ELISA), Annexin V assay, antibody array and immunoblotting. Statistical significance was analysed using one-way analysis of variance (ANOVA) and post hoc Dunnett's test. A p-value of less than 0.05 (p
Fulltext Functional Roles of JNK and p38 MAPK Signaling in Nasopharyngeal Carcinoma

Pua LJW, Mai CW, Chung FF, Khoo AS, Leong CO, Lim WM, et al.

Int J Mol Sci, 2022 Jan 20;23(3).
PMID: 35163030 DOI: 10.3390/ijms23031108

c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) family members integrate signals that affect proliferation, differentiation, survival, and migration in a cell context- and cell type-specific way. JNK and p38 MAPK activities are found upregulated in nasopharyngeal carcinoma (NPC). Studies have shown that activation of JNK and p38 MAPK signaling can promote NPC oncogenesis by mechanisms within the cancer cells and interactions with the tumor microenvironment. They regulate multiple transcription activities and contribute to tumor-promoting processes, ranging from cell proliferation to apoptosis, inflammation, metastasis, and angiogenesis. Current literature suggests that JNK and p38 MAPK activation may exert pro-tumorigenic functions in NPC, though the underlying mechanisms are not well documented and have yet to be fully explored. Here, we aim to provide a narrative review of JNK and p38 MAPK pathways in human cancers with a primary focus on NPC. We also discuss the potential therapeutic agents that could be used to target JNK and p38 MAPK signaling in NPC, along with perspectives for future works. We aim to inspire future studies further delineating JNK and p38 MAPK signaling in NPC oncogenesis which might offer important insights for better strategies in diagnosis, prognosis, and treatment decision-making in NPC patients.
Gene expression profiling of giant fibroadenomas of the breast

Yin Lee JP, Thomas AJ, Lum SK, Shamsudin NH, Hii LW, Mai CW, et al.

Surg Oncol, 2021 Jun;37:101536.
PMID: 33677364 DOI: 10.1016/j.suronc.2021.101536

INTRODUCTION: Fibroadenomas of the breast present as two phenotypic variants. The usual variety is 5 cm or less in diameter and there is another large variant called giant fibroadenoma which is greater than 5 cm in diameter. Despite of its large size, it is not malignant. The aim of our study is to determine whether this large variant is different from the usual fibroadenoma in terms of its biological pathways and biomarkers.
METHODS: mRNA was extracted from 44 fibroadenomas and 36 giant fibroadenomas, and transcriptomic profiling was performed to identify up- and down-regulated genes in the giant fibroadenomas as compared to the fibroadenomas.
RESULTS: A total of 40 genes were significantly up-regulated and 18 genes were significantly down-regulated in the giant fibroadenomas as compared to the fibroadenomas of the breast. The top 5 up-regulated genes were FN1, IL3, CDC6, FGF8 and BMP8A. The top 5 down-regulated genes were TNR, CDKN2A, COL5A1, THBS4 and BMPR1B. The differentially expressed genes (DEGs) were found to be associated with 5 major canonical pathways involved in cell growth (PI3K-AKT, cell cycle regulation, WNT, and RAS signalling) and immune response (JAK-STAT signalling). Further analyses using 3 supervised learning algorithms identified an 8-gene signature (FN1, CDC6, IL23A, CCNA1, MCM4, FLT1, FGF22 and COL5A1) that could distinguish giant fibroadenomas from fibroadenomas with high predictive accuracy.
CONCLUSION: Our findings demonstrated that the giant fibroadenomas are biologically distinct to fibroadenomas of the breast with overexpression of genes involved in the regulation of cell growth and immune response.
Fulltext Impact of Microplastics and Nanoplastics on Human Health

Yee MS, Hii LW, Looi CK, Lim WM, Wong SF, Kok YY, et al.

Nanomaterials (Basel), 2021 Feb 16;11(2).
PMID: 33669327 DOI: 10.3390/nano11020496

Plastics have enormous impacts to every aspect of daily life including technology, medicine and treatments, and domestic appliances. Most of the used plastics are thrown away by consumers after a single use, which has become a huge environmental problem as they will end up in landfill, oceans and other waterways. These plastics are discarded in vast numbers each day, and the breaking down of the plastics from micro- to nano-sizes has led to worries about how toxic these plastics are to the environment and humans. While, there are several earlier studies reported the effects of micro- and nano-plastics have on the environment, there is scant research into their impact on the human body at subcellular or molecular levels. In particular, the potential of how nano-plastics move through the gut, lungs and skin epithelia in causing systemic exposure has not been examined thoroughly. This review explores thoroughly on how nanoplastics are created, how they behave/breakdown within the environment, levels of toxicity and pollution of these nanoplastics, and the possible health impacts on humans, as well as suggestions for additional research. This paper aims to inspire future studies into core elements of micro- and nano-plastics, the biological reactions caused by their specific and unusual qualities.
Identification of inhibitors synergizing gemcitabine sensitivity in the squamous subtype of pancreatic ductal adenocarcinoma (PDAC)

Er JL, Goh PN, Lee CY, Tan YJ, Hii LW, Mai CW, et al.

Apoptosis, 2018 Jun;23(5-6):343-355.
PMID: 29740790 DOI: 10.1007/s10495-018-1459-6

Pancreatic adenocarcinoma (PDAC) is a highly aggressive cancer with a high chance of recurrence, limited treatment options, and poor prognosis. A recent study has classified pancreatic cancers into four molecular subtypes: (1) squamous, (2) immunogenic, (3) pancreatic progenitor and (4) aberrantly differentiated endocrine exocrine. Among all the subtypes, the squamous subtype has the worst prognosis. This study aims to utilize large scale genomic datasets and computational systems biology to identify potential drugs targeting the squamous subtype of PDAC through combination therapy. Using the transcriptomic data available from the International Cancer Genome Consortium, Cancer Cell Line Encyclopedia and Connectivity Map, we identified 26 small molecules that could target the squamous subtype of PDAC. Among them include inhibitors targeting the SRC proto-oncogene (SRC) and the mitogen-activated protein kinase kinase 1/2 (MEK1/2). Further analyses demonstrated that the SRC inhibitors (dasatinib and PP2) and MEK1/2 inhibitor (pimasertib) synergized gemcitabine sensitivity specifically in the squamous subtype of PDAC cells (SW1990 and BxPC3), but not in the PDAC progenitor cells (AsPC1). Further analysis revealed that the synergistic effects are dependent on SRC or MEK1/2 activities, as overexpression of SRC or MEK1/2 completely abrogated the synergistic effects SRC inhibitors (dasatinib and PP2) and MEK1/2 inhibitor (pimasertib). In contrast, no significant toxicity was observed in the MRC5 human lung fibroblast and ARPE-19 human retinal pigment epithelial cells. Together, our findings suggest that combinations of SRC or MEK inhibitors with gemcitabine possess synergistic effects on the squamous subtype of PDAC cells and warrant further investigation.
Fulltext Inhibition of Janus Kinase 1 synergizes docetaxel sensitivity in prostate cancer cells

Nalairndran G, Chung I, Abdul Razack AH, Chung FF, Hii LW, Lim WM, et al.

J Cell Mol Med, 2021 Sep;25(17):8187-8200.
PMID: 34322995 DOI: 10.1111/jcmm.16684

Prostate cancer (PCa) is the second most common malignancy and is the fifth leading cause of cancer mortality among men globally. Docetaxel-based therapy remains the first-line treatment for metastatic castration-resistant prostate cancer. However, dose-limiting toxicity including neutropenia, myelosuppression and neurotoxicity is the major reason for docetaxel dose reductions and fewer cycles administered, despite a recent study showing a clear survival benefit with increased total number of docetaxel cycles in PCa patients. Although previous studies have attempted to improve the efficacy and reduce docetaxel toxicity through drug combination, no drug has yet demonstrated improved overall survival in clinical trial, highlighting the challenges of improving the activity of docetaxel monotherapy in PCa. Herein, we identified 15 lethality hits for which inhibition could enhance docetaxel sensitivity in PCa cells via a high-throughput kinome-wide loss-of-function screen. Further drug-gene interactions analyses identified Janus kinase 1 (JAK1) as a viable druggable target with existing experimental inhibitors and FDA-approved drugs. We demonstrated that depletion of endogenous JAK1 enhanced docetaxel-induced apoptosis in PCa cells. Furthermore, inhibition of JAK1/2 by baricitinib and ruxolitinib synergizes docetaxel sensitivity in both androgen receptor (AR)-negative DU145 and PC3 cells, but not in the AR-positive LNCaP cells. In contrast, no synergistic effects were observed in cells treated with JAK2-specific inhibitor, fedratinib, suggesting that the synergistic effects are mainly mediated through JAK1 inhibition. In conclusion, the combination therapy with JAK1 inhibitors and docetaxel could be a useful therapeutic strategy in the treatment of prostate cancers.
Fulltext Mutant p53-R273H mediates cancer cell survival and anoikis resistance through AKT-dependent suppression of BCL2-modifying factor (BMF)

Tan BS, Tiong KH, Choo HL, Chung FF, Hii LW, Tan SH, et al.

Cell Death Dis, 2015;6:e1826.
PMID: 26181206 DOI: 10.1038/cddis.2015.191

p53 is the most frequently mutated tumor-suppressor gene in human cancers. Unlike other tumor-suppressor genes, p53 mutations mainly occur as missense mutations within the DNA-binding domain, leading to the expression of full-length mutant p53 protein. Mutant p53 proteins not only lose their tumor-suppressor function, but may also gain new oncogenic functions and promote tumorigenesis. Here, we showed that silencing of endogenous p53-R273H contact mutant, but not p53-R175H conformational mutant, reduced AKT phosphorylation, induced BCL2-modifying factor (BMF) expression, sensitized BIM dissociation from BCL-XL and induced mitochondria-dependent apoptosis in cancer cells. Importantly, cancer cells harboring endogenous p53-R273H mutant were also found to be inherently resistant to anoikis and lack BMF induction following culture in suspension. Underlying these activities is the ability of p53-R273H mutant to suppress BMF expression that is dependent on constitutively active PI3K/AKT signaling. Collectively, these findings suggest that p53-R273H can specifically drive AKT signaling and suppress BMF expression, resulting in enhanced cell survivability and anoikis resistance. These findings open the possibility that blocking of PI3K/AKT will have therapeutic benefit in mutant p53-R273H expressing cancers.
Fulltext Cudraflavone C Induces Tumor-Specific Apoptosis in Colorectal Cancer Cells through Inhibition of the Phosphoinositide 3-Kinase (PI3K)-AKT Pathway

Soo HC, Chung FF, Lim KH, Yap VA, Bradshaw TD, Hii LW, et al.

PLoS One, 2017;12(1):e0170551.
PMID: 28107519 DOI: 10.1371/journal.pone.0170551

Cudraflavone C (Cud C) is a naturally-occurring flavonol with reported anti-proliferative activities. However, the mechanisms by which Cud C induced cytotoxicity have yet to be fully elucidated. Here, we investigated the effects of Cud C on cell proliferation, caspase activation andapoptosis induction in colorectal cancer cells (CRC). We show that Cud C inhibits cell proliferation in KM12, Caco-2, HT29, HCC2998, HCT116 and SW48 CRC but not in the non-transformed colorectal epithelial cells, CCD CoN 841. Cud C induces tumor-selective apoptosis via mitochondrial depolarization and activation of the intrinsic caspase pathway. Gene expression profiling by microarray analyses revealed that tumor suppressor genes EGR1, HUWE1 and SMG1 were significantly up-regulated while oncogenes such as MYB1, CCNB1 and GPX2 were down-regulated following treatment with Cud C. Further analyses using Connectivity Map revealed that Cud C induced a gene signature highly similar to that of protein synthesis inhibitors and phosphoinositide 3-kinase (PI3K)-AKT inhibitors, suggesting that Cud C might inhibit PI3K-AKT signaling. A luminescent cell free PI3K lipid kinase assay revealed that Cud C significantly inhibited p110β/p85α PI3K activity, followed by p120γ, p110δ/p85α, and p110α/p85α PI3K activities. The inhibition by Cud C on p110β/p85α PI3K activity was comparable to LY-294002, a known PI3K inhibitor. Cud C also inhibited phosphorylation of AKT independent of NFκB activity in CRC cells, while ectopic expression of myristoylated AKT completely abrogated the anti-proliferative effects, and apoptosis induced by Cud C in CRC. These findings demonstrate that Cud C induces tumor-selective cytotoxicity by targeting the PI3K-AKT pathway. These findings provide novel insights into the mechanism of action of Cud C, and indicate that Cud C further development of Cud C derivatives as potential therapeutic agents is warranted.
Novel 2-Benzoyl-6-(2,3-Dimethoxybenzylidene)-Cyclohexenol Confers Selectivity toward Human MLH1 Defective Cancer Cells through Synthetic Lethality

Song DSS, Leong SW, Ng KW, Abas F, Shaari K, Leong CO, et al.

SLAS Discov, 2019 06;24(5):548-562.
PMID: 30897027 DOI: 10.1177/2472555219831405

DNA mismatch repair (MMR) deficiency has been associated with a higher risk of developing colorectal, endometrial, and ovarian cancer, and confers resistance in conventional chemotherapy. In addition to the lack of treatment options that work efficaciously on these MMR-deficient cancer patients, there is a great need to discover new drug leads for this purpose. In this study, we screened through a library of commercial and semisynthetic natural compounds to identify potential synthetic lethal drugs that may selectively target MLH1 mutants using MLH1 isogenic colorectal cancer cell lines and various cancer cell lines with known MLH1 status. We identified a novel diarylpentanoid analogue, 2-benzoyl-6-(2,3-dimethoxybenzylidene)-cyclohexenol, coded as AS13, that demonstrated selective toxicity toward MLH1-deficient cancer cells. Subsequent analysis suggested AS13 induced elevated levels of oxidative stress, resulting in DNA damage where only the proficient MLH1 cells were able to be repaired and hence escaping cellular death. While AS13 is modest in potency and selectivity, this discovery has the potential to lead to further drug development that may offer better treatment options for cancer patients with MLH1 deficiency.
Fulltext Survival predictors in paraquat intoxification and role of immunosuppression

Koh KH, Tan CH, Hii LW, Lee J, Ngu LL, Chai AJ, et al.

Toxicol Rep, 2014;1:490-495.
PMID: 28962262 DOI: 10.1016/j.toxrep.2014.06.010

Paraquat poisoning resulted in multiorgan failure and is associated with high mortality. We audited 83 historical cases of paraquat poisoning in past 2 years treated with conventional decontamination and supportive treatment, followed by enrolling 85 patients over a 2 year period into additional immunosuppression with intravenous (i.v.) methylprednisolone and i.v. cyclophosphamide. Our results showed that age, poor renal function and leucocytosis are the main predictors of fatal outcome. Immunosuppression regime rendered higher survival (6 out of 17 patients (35.3%)) versus historical control (1 out of 18 patients (5.6%)) (p = 0.041) in the cohort with admission eGFR < 50 ml/min/1.73 m(2) and WBC count > 11,000/μL. In contrast, there was no difference in survival with immunosuppression regime (38 out of 64 patients (59.4%)) compared to historical control (30 out of 52 patients (57.7%)) (p = 0.885) in those with eGFR > 50 ml/min/1.73 m(2) or WBC < 11,000/μL at presentation. Multivariable logistic regression showed survival probability = exp(logit)/(1 + exp(logit)), in which logit = 13.962 - (0.233 × ln(age (year))) - (1.344 × ln(creatinine (μmol/L))) - (1.602 × ln(rise in creatinine (μmol/day))) - (0.614 × ln(WBC (,000/μL))) + (2.021 × immunosuppression) and immunosuppression = 1 if given and 0 if not. Immunosuppression therapy yielded odds ratio of 0.132 (95% confidential interval: 0.029-0.603, p = 0.009). In conclusion, immunosuppression therapy with intravenous methylprednisolone and cyclophosphamide may counteract immune mediated inflammation after paraquat poisoning and improve survival of patients with admission eGFR < 50 ml/min/1.73 m(2) and WBC count > 11,000/μL.
Fulltext Discovery of Ruthenium(II) Metallocompound and Olaparib Synergy for Cancer Combination Therapy

Yusoh NA, Tiley PR, James SD, Harun SN, Thomas JA, Saad N, et al.

J Med Chem, 2023 May 25;66(10):6922-6937.
PMID: 37185020 DOI: 10.1021/acs.jmedchem.3c00322

Synergistic drug combinations can extend the use of poly(ADP-ribose) polymerase inhibitors (PARPi) such as Olaparib to BRCA-proficient tumors and overcome acquired or de novo drug resistance. To identify new synergistic combinations for PARPi, we screened a "micro-library" comprising a mix of commercially available drugs and DNA-binding ruthenium(II) polypyridyl complexes (RPCs) for Olaparib synergy in BRCA-proficient triple-negative breast cancer cells. This identified three hits: the natural product Curcumin and two ruthenium(II)-rhenium(I) polypyridyl metallomacrocycles. All combinations identified were effective in BRCA-proficient breast cancer cells, including an Olaparib-resistant cell line, and spheroid models. Mechanistic studies indicated that synergy was achieved via DNA-damage enhancement and resultant apoptosis. Combinations showed low cytotoxicity toward non-malignant breast epithelial cells and low acute and developmental toxicity in zebrafish embryos. This work identifies RPC metallomacrocycles as a novel class of agents for cancer combination therapy and provides a proof of concept for the inclusion of metallocompounds within drug synergy screens.
Fulltext Sphingosine Kinase 1 Regulates the Survival of Breast Cancer Stem Cells and Non-stem Breast Cancer Cells by Suppression of STAT1

Hii LW, Chung FF, Mai CW, Yee ZY, Chan HH, Raja VJ, et al.

Cells, 2020 04 04;9(4).
PMID: 32260399 DOI: 10.3390/cells9040886

Cancer stem cells (CSCs) represent rare tumor cell populations capable of self-renewal, differentiation, and tumor initiation and are highly resistant to chemotherapy and radiotherapy. Thus, therapeutic approaches that can effectively target CSCs and tumor cells could be the key to efficient tumor treatment. In this study, we explored the function of SPHK1 in breast CSCs and non-CSCs. We showed that RNAi-mediated knockdown of SPHK1 inhibited cell proliferation and induced apoptosis in both breast CSCs and non-CSCs, while ectopic expression of SPHK1 enhanced breast CSC survival and mammosphere forming efficiency. We identified STAT1 and IFN signaling as key regulatory targets of SPHK1 and demonstrated that an important mechanism by which SPHK1 promotes cancer cell survival is through the suppression of STAT1. We further demonstrated that SPHK1 inhibitors, FTY720 and PF543, synergized with doxorubicin in targeting both breast CSCs and non-CSCs. In conclusion, we provide important evidence that SPHK1 is a key regulator of cell survival and proliferation in breast CSCs and non-CSCs and is an attractive target for the design of future therapies.
Fulltext Phosphoinositide-dependent Kinase-1 (PDPK1) regulates serum/glucocorticoid-regulated Kinase 3 (SGK3) for prostate cancer cell survival

Nalairndran G, Hassan Abdul Razack A, Mai CW, Fei-Lei Chung F, Chan KK, Hii LW, et al.

J Cell Mol Med, 2020 Oct;24(20):12188-12198.
PMID: 32926495 DOI: 10.1111/jcmm.15876

Prostate cancer (PCa) is the most common malignancy and is the second leading cause of cancer among men globally. Using a kinome-wide lentiviral small-hairpin RNA (shRNA) library screen, we identified phosphoinositide-dependent kinase-1 (PDPK1) as a potential mediator of cell survival in PCa cells. We showed that knock-down of endogenous human PDPK1 induced significant tumour-specific cell death in PCa cells (DU145 and PC3) but not in the normal prostate epithelial cells (RWPE-1). Further analyses revealed that PDPK1 mediates cancer cell survival predominantly via activation of serum/glucocorticoid-regulated kinase 3 (SGK3). Knock-down of endogenous PDPK1 in DU145 and PC3 cells significantly reduced SGK3 phosphorylation while ectopic expression of a constitutively active SGK3 completely abrogated the apoptosis induced by PDPK1. In contrast, no such effect was observed in SGK1 and AKT phosphorylation following PDPK1 knock-down. Importantly, PDPK1 inhibitors (GSK2334470 and BX-795) significantly reduced tumour-specific cell growth and synergized docetaxel sensitivity in PCa cells. In summary, our results demonstrated that PDPK1 mediates PCa cells' survival through SGK3 signalling and suggest that inactivation of this PDPK1-SGK3 axis may potentially serve as a novel therapeutic intervention for future treatment of PCa.
Fulltext Fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) autocrine enhance breast cancer cells survival

Tiong KH, Tan BS, Choo HL, Chung FF, Hii LW, Tan SH, et al.

Oncotarget, 2016 Sep 06;7(36):57633-57650.
PMID: 27192118 DOI: 10.18632/oncotarget.9328

Basal-like breast cancer is an aggressive tumor subtype with poor prognosis. The discovery of underlying mechanisms mediating tumor cell survival, and the development of novel agents to target these pathways, is a priority for patients with basal-like breast cancer. From a functional screen to identify key drivers of basal-like breast cancer cell growth, we identified fibroblast growth factor receptor 4 (FGFR4) as a potential mediator of cell survival. We found that FGFR4 mediates cancer cell survival predominantly via activation of PI3K/AKT. Importantly, a subset of basal-like breast cancer cells also secrete fibroblast growth factor 19 (FGF19), a canonical ligand specific for FGFR4. siRNA-mediated silencing of FGF19 or neutralization of extracellular FGF19 by anti-FGF19 antibody (1A6) decreases AKT phosphorylation, suppresses cancer cell growth and enhances doxorubicin sensitivity only in the FGFR4+/FGF19+ breast cancer cells. Consistently, FGFR4/FGF19 co-expression was also observed in 82 out of 287 (28.6%) primary breast tumors, and their expression is strongly associated with AKT phosphorylation, Ki-67 staining, higher tumor stage and basal-like phenotype. In summary, our results demonstrated the presence of an FGFR4/FGF19 autocrine signaling that mediates the survival of a subset of basal-like breast cancer cells and suggest that inactivation of this autocrine loop may potentially serve as a novel therapeutic intervention for future treatment of breast cancers.
Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) combination therapy through impairing intracellular ATP production and DNA repair in breast cancer stem cells

Soo JS, Ng CH, Tan SH, Malik RA, Teh YC, Tan BS, et al.

Apoptosis, 2015 Oct;20(10):1373-87.
PMID: 26276035 DOI: 10.1007/s10495-015-1158-5

Metformin, an AMPK activator, has been reported to improve pathological response to chemotherapy in diabetic breast cancer patients. To date, its mechanism of action in cancer, especially in cancer stem cells (CSCs) have not been fully elucidated. In this study, we demonstrated that metformin, but not other AMPK activators (e.g. AICAR and A-769662), synergizes 5-fluouracil, epirubicin, and cyclophosphamide (FEC) combination chemotherapy in non-stem breast cancer cells and breast cancer stem cells. We show that this occurs through an AMPK-dependent mechanism in parental breast cancer cell lines. In contrast, the synergistic effects of metformin and FEC occurred in an AMPK-independent mechanism in breast CSCs. Further analyses revealed that metformin accelerated glucose consumption and lactate production more severely in the breast CSCs but the production of intracellular ATP was severely hampered, leading to a severe energy crisis and impairs the ability of CSCs to repair FEC-induced DNA damage. Indeed, addition of extracellular ATP completely abrogated the synergistic effects of metformin on FEC sensitivity in breast CSCs. In conclusion, our results suggest that metformin synergizes FEC sensitivity through distinct mechanism in parental breast cancer cell lines and CSCs, thus providing further evidence for the clinical relevance of metformin for the treatment of cancers.
Monomeric, Dimeric, and Trimeric Tropane Alkaloids from Pellacalyx saccardianus

Chan ZY, Krishnan P, Modaresi SM, Hii LW, Mai CW, Lim WM, et al.

J Nat Prod, 2021 08 27;84(8):2272-2281.
PMID: 34342431 DOI: 10.1021/acs.jnatprod.1c00374

Seven new tropane alkaloids, including five monomeric (1-5), one dimeric (6), and one trimeric (7) 3α-nortropane ester, along with two known monomeric nortropane alkaloids (8 and 9), were isolated from the leaves and bark of Pellacalyx saccardianus. Their structures, including the absolute configuration of the enantiomeric pair of (±)-6, were elucidated by comprehensive spectroscopic analyses. Alkaloids 6 and 7 showed cytotoxicity toward human pancreatic cancer cell lines (AsPC-1, BxPC3, PANC-1, and SW1990). Alkaloids 1, 4, and 9 induced a smooth muscle relaxation effect comparable to that of atropine (Emax 106.1 ± 7.5%, 97.0 ± 5.2%, 100.9 ± 1.4%, 111.7 ± 1.7%, respectively) on isolated rat tracheal rings.
Fulltext Jerantinine A induces tumor-specific cell death through modulation of splicing factor 3b subunit 1 (SF3B1)

Chung FF, Tan PF, Raja VJ, Tan BS, Lim KH, Kam TS, et al.

Sci Rep, 2017 02 15;7:42504.
PMID: 28198434 DOI: 10.1038/srep42504

Precursor mRNA (pre-mRNA) splicing is catalyzed by a large ribonucleoprotein complex known as the spliceosome. Numerous studies have indicated that aberrant splicing patterns or mutations in spliceosome components, including the splicing factor 3b subunit 1 (SF3B1), are associated with hallmark cancer phenotypes. This has led to the identification and development of small molecules with spliceosome-modulating activity as potential anticancer agents. Jerantinine A (JA) is a novel indole alkaloid which displays potent anti-proliferative activities against human cancer cell lines by inhibiting tubulin polymerization and inducing G2/M cell cycle arrest. Using a combined pooled-genome wide shRNA library screen and global proteomic profiling, we showed that JA targets the spliceosome by up-regulating SF3B1 and SF3B3 protein in breast cancer cells. Notably, JA induced significant tumor-specific cell death and a significant increase in unspliced pre-mRNAs. In contrast, depletion of endogenous SF3B1 abrogated the apoptotic effects, but not the G2/M cell cycle arrest induced by JA. Further analyses showed that JA stabilizes endogenous SF3B1 protein in breast cancer cells and induced dissociation of the protein from the nucleosome complex. Together, these results demonstrate that JA exerts its antitumor activity by targeting SF3B1 and SF3B3 in addition to its reported targeting of tubulin polymerization.

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