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[Upregulation of MHC I Antigen Processing Machinery Gene Expression in Breast Cancer Cells by Trichostatin A]

Murtadha AH, Sharudin NA, Azahar IIM, Che Has AT, Mokhtar NF

Mol Biol (Mosk), 2023;57(6):21-30.
PMID: 38062971

Epigenetic alterations associated with cancer have been shown to facilitate tumorigenesis and promote metastasis. In the study of cancer metastasis, epigenetics has been revealed to play a crucial role in supporting tumour immune evasion. As a result, epigenetic drugs have been identified as potential agents to activate anti-tumour immune responses and reverse tumour immunologically tolerant states. Mounting evidence is showing aberrant expression of MHC class I antigen processing molecules in cancers and their upregulation as a potential indicator for anti-tumour immunity. In this study, we demonstrate that the epigenetic drug Trichostatin A (TSA), a histone deacetylase inhibitor, can restore MHC I antigen presentation machinery (MHC I APM) genes in human breast cancer cells (MCF-7). Treatment with TSA resulted in the upregulation of MHC I, B2M, and PSMB9 in MCF-7 monolayer cells, and MHC I, B2M, PSMB9, PSMB8, TAP1, and TAP2 in MCF-7 spheroid cells. Interestingly, treatment with TSA also increased CD274 expression in these cells and enhanced the invasion ability of the MCF-7 spheroid. This aggressive behaviour was confirmed by increased expression of metastatic-related genes, nNav1.5 and MMP1. In summary, although the restoration of MHCIAPM expression was achieved by TSA, the upregulation of metastatic genes and CD274 also enhanced the invasion ability of breast cancer cells. These findings suggest the need for careful consideration when utilizing epigenetic drugs for breast cancer therapy.
Fulltext The NF-κB Transcriptional Network Is a High-Dose Vitamin C-Targetable Vulnerability in Breast Cancer

Mussa A, Afolabi HA, Syed NH, Talib M, Murtadha AH, Hajissa K, et al.

Biomedicines, 2023 Mar 30;11(4).
PMID: 37189677 DOI: 10.3390/biomedicines11041060

Breast cancer (BC) is the most common cancer type among women with a distinct clinical presentation, but the survival rate remains moderate despite advances in multimodal therapy. Consequently, a deeper understanding of the molecular etiology is required for the development of more effective treatments for BC. The relationship between inflammation and tumorigenesis is well established, and the activation of the pro-inflammatory transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is frequently identified in BC. Constitutive NF-κB activation is linked to cell survival, metastasis, proliferation, and hormonal, chemo-, and radiotherapy resistance. Moreover, the crosstalk between NF-κB and other transcription factors is well documented. It is reported that vitamin C plays a key role in preventing and treating a number of pathological conditions, including cancer, when administered at remarkably high doses. Indeed, vitamin C can regulate the activation of NF-κB by inhibiting specific NF-κB-dependent genes and multiple stimuli. In this review, we examine the various NF-κB impacts on BC development. We also provide some insight into how the NF-κB network may be targeted as a potential vulnerability by using natural pro-oxidant therapies such as vitamin C.
Pharmacological Vitamin C-induced high H2O2 generation mediates apoptotic cell death by caspase 3/7 activation in breast cancer tumor spheroids

Mussa A, Hamid M, Hajissa K, Murtadha AH, Al-Hatamleh MAI, Mokhtar NF, et al.

J Transl Med, 2025 Jan 08;23(1):31.
PMID: 39780231 DOI: 10.1186/s12967-024-06016-7

BACKGROUND: Pharmacological vitamin C (Vit-C), or high-dose Vit-C has recently gained attention as a potential cancer therapeutic. However, the anticancer activity of Vit-C has not been investigated in realistic 3D models of human cancers, especially with respect to breast cancer (BC), and its potential benefits remain under debate. Herein, we investigate the activity and mechanism of action of pharmacological Vit-C on two BC tumor spheroids.
METHODS: We developed two distinct types of BC tumor spheroids from MDA-MB-231 and MCF-7 cells. The spheroids underwent treatment with a range of concentrations of pharmacological Vit-C (1, 5, 10, 15, and 20 mM). Assessments were conducted to determine the cell viability, H2O2 levels, glutathione-to-glutathione disulfide (GSH/GSSG) ratios, and apoptosis. Both flow cytometry analyses of Annexin V/PI staining and caspase3/7 activity assay were used to check apoptosis.
RESULTS: We showed that Vit-C induced dose-dependent cell death in both types of tumor spheroids, primarily driven by elevated H2O2 production and a concomitant oxidative stress imbalance induced by the GSH depletion. The high levels of H2O2 generated by Vit-C triggered the apoptosis of spheroids. In MCF-7 spheroids, Vit-C-induced H2O2 production was higher, with a more pronounced decrease in the GSH/GSSG ratio, indicating greater susceptibility to oxidative stress-induced cell death. However, MDA-MB-231 spheroids exhibited a more severe cytotoxic response.
CONCLUSIONS: This study reveals that Vit-C induces oxidative stress-mediated cell death in both non-aggressive and aggressive BC spheroids. Unlike traditional in vitro studies, this work provides novel insights into the response of two BC tumor subtypes to Vit-C, demonstrating its potential as a targeted common therapy for BC.
Prognostic prospect of soluble programmed cell death ligand-1 in cancer management

Khairil Anwar NA, Mohd Nazri MN, Murtadha AH, Mohd Adzemi ER, Balakrishnan V, Mustaffa KMF, et al.

Acta Biochim Biophys Sin (Shanghai), 2021 Jul 28;53(8):961-978.
PMID: 34180502 DOI: 10.1093/abbs/gmab077

Aggressive tissue biopsy is commonly unavoidable in the management of most suspected tumor cases to conclusively verify the presence of cancerous cells through histological assessment. The extracted tissue is also immunostained for detection of antigens (tissue tumor markers) of potential prognostic or therapeutic importance to assist in treatment decision. Although liquid biopsies can be a powerful tool for monitoring treatment response, they are still excluded from standard cancer diagnostics, and their utility is still being debated in the scientific community. With a myriad of soluble tissue tumor markers now being discovered, liquid biopsies could completely change the current paradigms of cancer management. Recently, soluble programmed cell death ligand-1 (sPD-L1), which is found in the peripheral blood, i.e. serum and plasma, has shown potential as a pre-therapeutic predictive marker as well as a prognostic biomarker to monitor treatment efficacy. Thus, this review focuses on the emergence of sPD-L1 and promising technologies for its detection in order to support liquid biopsies for future cancer management.