Browsing by Author "Alzahrani, Amal Hamdan"

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ENHANCEMENT OF MDM2 INHIBITORY EFFECTS THROUGH BLOCKING NUCLEAR EXPORT MECHANISMS
(2023-04-26) Alzahrani, Amal Hamdan; Appu, Rathinavelu
Ovarian cancer is one of the most serious health concerns worldwide, particularly among postmenopausal women. It has been confirmed that ovarian cancer develops to the metastatic type in 75% of patients and is associated with a higher mortality rate compared to other gynecological cancer types. Despite extensive research efforts over the last few decades, patients with ovarian cancer still suffer from frequent relapses and chemotherapy resistance. A well know guardian of the genome called p53 is a nuclear transcriptional regulator involved in multiple cellular processes to maintain homeostasis and genome integrity. Wild-type p53 activates DNA repair mechanisms, arrests cell growth by halting the cell cycle at the G1/S or G2/M phase and induces apoptosis if unrepairable DNA damage occurs in the cells. Furthermore, it regulates cell adhesion, motility, and epithelial- to-mesenchymal transition (EMT), which are commonly correlated to ovarian cancer aggressiveness. In ovarian cancer, over 90% of cancer cells are signified by mutations or inactivation of the p53 gene, which is responsible for many challenges seen during ovarian cancer treatment. It has been demonstrated with ample evidence that EMT is also crucial in ovarian cancer's progression and metastasis. However, the molecular mechanism that maintains the EMT of ovarian cancer cells is still being explored. Therefore, this study aimed to investigate whether activating p53 can induce cell death and reverse EMT characteristics in ovarian cancer cells. Overexpression of MDM2 (mouse double minute 2) oncoprotein is associated with the aggressiveness of many malignancies, including ovarian cancer. Among the various therapeutics in development, RG7388 (MDM2 inhibitor) is a known reactivator of p53 function and therefore has been pursued with high interest for cancer therapy. In addition, Selinexor, a selective inhibitor of nuclear export (SINE), is known to cause an accumulation of p53 inside the nucleus and therefore is being explored as a therapy potentiating agent in combination treatments. Accordingly, this study was conducted to assess the efficacy of RG7388 in combination with Selinexor for inducing cell cycle arrest and cell death or reversing EMT in A2780 ovarian cancer cells through upregulation of p53. Interestingly, a synergistic effect was observed when Selinexor and RG7388 were combined to induce apoptotic cell death through caspase 3/7 activation and PARP cleavage. The upregulation of p21 and downregulation of CDK6 and AURKB further confirmed the induction of cell cycle arrest. Additionally, the reversal of EMT by restoring epithelial levels of E-cadherin and N-cadherin, as well as by downregulating CD44, was achieved through modulation of ZEB1, Slug, and Snail. The overall efficacy observed in our study is attributed to the ability of p53 to trigger cell cycle arrest and apoptosis. Our study has yielded a valuable strategy for blocking nuclear export mechanisms in ovarian cancer cells to enhance MDM2 inhibitor-mediated effects.
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