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Mechanisms of sphingosine 1-phosphate receptor signalling in cancer

Patmanathan SN, Wang W, Yap LF, Herr DR, Paterson IC

Cell Signal, 2017 06;34:66-75.
PMID: 28302566 DOI: 10.1016/j.cellsig.2017.03.002

S1P is a small bioactive lipid which exerts its effects following binding to a family of five G protein-coupled receptors, known as S1P1-5. Following receptor activation, multiple signalling cascades are activated, allowing S1P to regulate a range of cellular processes, such as proliferation, apoptosis, migration and angiogenesis. There is strong evidence implicating the involvement of S1P receptors (S1PRs) in cancer progression and the oncogenic effects of S1P can result from alterations in the expression of one or more of the S1PRs and/or the enzymes that regulate the levels of S1P. However, cooperativity between the individual S1PRs, functional interactions with receptor tyrosine kinases and the sub-cellular localisation of the S1PRs within tumour cells also appear to play a role in mediating the effects of S1PR signalling during carcinogenesis. Here we review what is known regarding the role of individual S1PRs in cancer and discuss the recent evidence to suggest cross-talk between the S1PRs and other cellular signalling pathways in cancer. We will also discuss the therapeutic potential of targeting the S1PRs and their downstream signalling pathways for the treatment of cancer.

Matched MeSH terms: Receptor Protein-Tyrosine Kinases/metabolism
Common ALK gene rearrangement in Asian CD30+ anaplastic large cell lymphoma: an immunohistochemical and fluorescence in situ hybridisation (FISH) study on paraffin-embedded tissue

Tai YC, Kim LH, Peh SC

Pathology, 2003 Oct;35(5):436-43.
PMID: 14555389

AIMS: The most common recurrent genetic aberration in anaplastic large cell lymphoma (ALCL) is translocation involving the ALK gene that results in ectopic expression of ALK protein in lymphoid tissue. This study aims to investigate the frequency of ALK gene rearrangement in a series of Asian ALCL.
METHODS: ALK gene rearrangement was detected by immunostaining of ALK protein and fluorescence in situ hybridisation (FISH) targeting at the 2p23 region.
RESULTS: The expression of ALK protein was detected in 24/34 (71%) of the cases, and it was significantly higher in childhood cases (100%) when compared to adult cases (47%). The analyses by FISH were consistent with the results from immunostaining of ALK protein, but the analyses were only successful in 15/34 (44%) cases. FISH analyses detected extra copies of ALK gene in three cases, including one case that expressed ALK protein and showed 2p23 rearrangement.
CONCLUSIONS: The current series revealed a high frequency of ALK gene rearrangement, especially in the children. Immunostaining of ALK protein is a reliable indication of ALK gene rearrangement, and is superior to FISH. However, FISH analysis is useful in detecting other genetic aberrations that are not related to ALK gene rearrangement.

Matched MeSH terms: Protein-Tyrosine Kinases/metabolism
Fulltext Receptor tyrosine kinase (c-Kit) inhibitors: a potential therapeutic target in cancer cells

Abbaspour Babaei M, Kamalidehghan B, Saleem M, Huri HZ, Ahmadipour F

Drug Des Devel Ther, 2016;10:2443-59.
PMID: 27536065 DOI: 10.2147/DDDT.S89114

c-Kit, a receptor tyrosine kinase, is involved in intracellular signaling, and the mutated form of c-Kit plays a crucial role in occurrence of some cancers. The function of c-Kit has led to the concept that inhibiting c-Kit kinase activity can be a target for cancer therapy. The promising results of inhibition of c-Kit for treatment of cancers have been observed in some cancers such as gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, and other tumors, and these results have encouraged attempts toward improvement of using c-Kit as a capable target for cancer therapy. This paper presents the findings of previous studies regarding c-Kit as a receptor tyrosine kinase and an oncogene, as well as its gene targets and signaling pathways in normal and cancer cells. The c-Kit gene location, protein structure, and the role of c-Kit in normal cell have been discussed. Comprehending the molecular mechanism underlying c-Kit-mediated tumorogenesis is consequently essential and may lead to the identification of future novel drug targets. The potential mechanisms by which c-Kit induces cellular transformation have been described. This study aims to elucidate the function of c-Kit for future cancer therapy. In addition, it has c-Kit inhibitor drug properties and their functions have been listed in tables and demonstrated in schematic pictures. This review also has collected previous studies that targeted c-Kit as a novel strategy for cancer therapy. This paper further emphasizes the advantages of this approach, as well as the limitations that must be addressed in the future. Finally, although c-Kit is an attractive target for cancer therapy, based on the outcomes of treatment of patients with c-Kit inhibitors, it is unlikely that Kit inhibitors alone can lead to cure. It seems that c-Kit mutations alone are not sufficient for tumorogenesis, but do play a crucial role in cancer occurrence.

Matched MeSH terms: Receptor Protein-Tyrosine Kinases/metabolism*
Fulltext High intracellular Zn2+ ions modulate the VHR, ZAP-70 and ERK activities of LNCaP prostate cancer cells

Wong PF, Abubakar S

Cell Mol Biol Lett, 2008;13(3):375-90.
PMID: 18311544 DOI: 10.2478/s11658-008-0009-6

Malignant prostate tissues have markedly reduced zinc (Zn(2+)) contents in comparison to non-malignant tissues. In this study, we restored a high intracellular Zn(2+) level to LNCaP prostate cancer cells by culturing the cells in a growth medium supplemented with a supraphysiological concentration of Zn(2+) (10 microg/ml) over 5 weeks. The intracellular Zn(2+) level increased in the Zn(2+)-treated cells, and there was a marked increase in the presence of zincosomes, a Zn(2+)-specific intracellular organelle. The proliferation rate of the Zn(2+)-treated cells was markedly reduced. There was also a significant increase (36.6% +/- 6.4%) in the total tyrosine phosphorylated proteins. Vaccinia H1-related (VHR) phosphatase, zeta chain-associated protein-70 (ZAP-70) kinase and phosphorylated extracellular signal-regulated protein kinase 1 and 2 (p-ERK 1 and 2) were also present in higher abundance. Treatment with TPEN, which chelates Zn(2+), reduced the abundance of VHR phosphatase and ZAP-70 kinase, but increased the abundance of p-ERK 1. However, the TPEN treatment restored the Zn(2+)-treated LNCaP cell proliferation to a rate comparable to that of the non Zn(2+)-treated cells. These results highlight the importance of a high intracellular Zn(2+) content and the VHR/ZAP-70-associated pathways in the modulation of LNCaP prostate cancer cell growth.

Matched MeSH terms: Protein-Tyrosine Kinases/metabolism
Nitric oxide production by a murine macrophage cell line (RAW264.7 cells) stimulated with Aggregatibacter actinomycetemcomitans surface-associated material

Sosroseno W, Bird PS, Seymour GJ

Anaerobe, 2011 Oct;17(5):246-51.
PMID: 21736946 DOI: 10.1016/j.anaerobe.2011.06.006

Nitric oxide (NO) may play a crucial role in the pathogenesis of periodontal disease and, hence, the aim of the present study was to test the hypothesis that Aggregatibacter actinomycetemcomitans surface-associated material (SAM) stimulates inducible nitric oxide synthase (iNOS) activity and NO production by the murine macrophage cell line RAW264.7. Cells were stimulated with untreated or heat-treated A. actinomycetemcomitans SAM and with or without pre-treatment with L-N(6)-(1-Iminoethyl)-lysine (L-NIL) (an iNOS inhibitor), polymyxin B, interferon-gamma (IFN-γ) and Interleukin-4 (IL-4), IL-10, genistein [a protein tyrosine kinase (PTK) inhibitor], bisindolylmaleimide [a protein kinase C (PKC) inhibitor], bromophenacyl bromide (BPB) [a phospholipase A(2) (PLA2) inhibitor] or wortmannin [phosphatidylinositol 3-kinase (PI-3K) inhibitor]. The iNOS activity and nitrite production in the cell cultures were determined. Untreated but not heat-treated A. actinomycetemcomitans SAM-stimulated both iNOS activity and nitrite production in RAW264.7 cells. L-NIL, IL-4, IL-10, genistein, bisindolylmaleimide, or BPB, suppressed but IFN-γ enhanced both iNOS activity and nitrite production by A. actinomycetemcomitans SAM-stimulated cells. Wortmannin and polymyxin B failed to alter both iNOS activity or nitrite production by A. actinomycetemcomitans SAM treated cells. Therefore, the present study suggests that a heat-sensitive protein constituent(s) of A. actinomycetemcomitans SAM stimulates both iNOS activity and nitrite production by RAW264.7 cells in a cytokine, PTK, PKC, and PLA(2) but not PI-3K-dependent fashion.

Matched MeSH terms: Protein-Tyrosine Kinases/metabolism
Expression of DDR1 and DVL1 in invasive ductal and lobular breast carcinoma does not correlate with histological type, grade and hormone receptor status

Ameli F, Rose IM, Masir N

Asian Pac J Cancer Prev, 2015;16(6):2385-90.
PMID: 25824769

BACKGROUND: Invasive ductal (IDC) and lobular (ILC) carcinomas are the common histological types of breast carcinoma which are difficult to distinguish when poorly differentiated. Discoidin domain receptor (DDR1) and Drosophila dishevelled protein (DVL1) were recently suggested to differentiate IDC from ILC.
OBJECTIVES: To assess the expression of DDR1 and DVL1 and their association with histological type, grading and hormonal status of IDC and ILC.
MATERIALS AND METHODS: This cross sectional study was conducted on IDC and ILC breast tumours. Tumours were immunohistochemically stained for (DDR1) and (DVL1) as well as estrogen receptor (ER), progesterone receptor (PR) and C-erbB2 receptor. Demographic data including age and ethnicity were obtained from patient records.
RESULTS: A total of 51 cases (30 IDCs and 21 ILCs) were assessed. DDR1 and DVL1 expression was not significantly associated with histological type (p=0.57 and p=0.66 respectively). There was no association between DDR1 and DVL1 expression and tumour grade (p=0.32 and p=1.00 respectively), ER (p=0.62 and 0.50 respectively), PR (p=0.38 and p=0.63 respectively) and C-erbB2 expression (p=0.19 and p=0.33 respectively) in IDC. There was no association between DDR1 and DVL1 expression and tumour grade (p=0.52 and p=0.33 respectively), ER (p=0.06 and p=0.76 respectively), PR (p=0.61 and p=0.43 respectively) and C-erbB2 expression (p=0.58 and p=0.76 respectively) in ILC.
CONCLUSIONS: This study revealed that DDR1 and DVL1 are present in both IDC and ILC regardless of the tumour differentiation. More studies are needed to assess the potential of these two proteins in distinguishing IDC from ILC in breast tumours.

Matched MeSH terms: Receptor Protein-Tyrosine Kinases/metabolism*
Immunohistochemical localisation of RET and p53 mutant protein of thyroid lesions in a North-Eastern Malaysian population and its prognostic implications

Omar E, Madhavan M, Othman NH

Pathology, 2004 Apr;36(2):152-9.
PMID: 15203751

To investigate RET and p53 expression in local thyroid lesions, in order to shed light on the pathogenesis of papillary carcinoma and explain the high prevalence of this condition among the nodular hyperplasia (multi-nodular goitre) cases.

Matched MeSH terms: Receptor Protein-Tyrosine Kinases/metabolism*
Molecular process of glucose uptake and glycogen storage due to hamamelitannin via insulin signalling cascade in glucose metabolism

Issac PK, Guru A, Chandrakumar SS, Lite C, Saraswathi NT, Arasu MV, et al.

Mol Biol Rep, 2020 Sep;47(9):6727-6740.
PMID: 32809102 DOI: 10.1007/s11033-020-05728-5

Understanding the mechanism by which the exogenous biomolecule modulates the GLUT-4 signalling cascade along with the information on glucose metabolism is essential for finding solutions to increasing cases of diabetes and metabolic disease. This study aimed at investigating the effect of hamamelitannin on glycogen synthesis in an insulin resistance model using L6 myotubes. Glucose uptake was determined using 2-deoxy-D-[1-3H] glucose and glycogen synthesis were also estimated in L6 myotubes. The expression levels of key genes and proteins involved in the insulin-signaling pathway were determined using real-time PCR and western blot techniques. The cells treated with various concentrations of hamamelitannin (20 µM to 100 µM) for 24 h showed that, the exposure of hamamelitannin was not cytotoxic to L6 myotubes. Further the 2-deoxy-D-[1-3H] glucose uptake assay was carried out in the presence of wortmannin and Genistein inhibitor for studying the GLUT-4 dependent cell surface recruitment. Hamamelitannin exhibited anti-diabetic activity by displaying a significant increase in glucose uptake (125.1%) and glycogen storage (8.7 mM) in a dose-dependent manner. The optimum concentration evincing maximum activity was found to be 100 µm. In addition, the expression of key genes and proteins involved in the insulin signaling pathway was studied to be upregulated by hamamelitannin treatment. Western blot analysis confirmed the translocation of GLUT-4 protein from an intracellular pool to the plasma membrane. Therefore, it can be conceived that hamamelitannin exhibited an insulinomimetic effect by enhancing the glucose uptake and its further conversion into glycogen by regulating glucose metabolism.

Matched MeSH terms: Protein-Tyrosine Kinases/metabolism