TP53 gene is the most commonly mutated tumour suppressor in human malignancies. TP53 is mutated in more than 50% of all human cancers, with over 96% of high-grade serous ovarian cancer displaying changes at this locus. Mutations of TP53 gene is associated with malignant transformation and resistance to chemotherapy. In addition, previous studies have shown that ectopic expression of TP53 mutant form in breast cancer cells leads to increased transcription of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). This enzyme regulates the synthesis of geranylgeraniol which is used to post-translationally modify small GTPase oncogenes. HMGCR is itself considered to be a metabolic oncogene. Statins, which inhibit HMGCR, are potential cancer therapeutics which can cause ovarian cancer (OC) cell apoptosis and regression of xenografts.
The level of mevalonate pathway (MP) enzymes evaluated in panel of OC cell lines using immunoblotting. in addition, MP enzymes expression were evaluate using qPCR following ectopic expression of wild-type and R248W, R175H, and R273H p53 variants in Skov-3 cells and after inhibition of TP53 expression using siRNA directed to TP53 mRNA in Ovcar-3 cells.
We confirmed that the expression of HMGCR is higher in OC cell lines than in normal epithelial ovarian cells. The level of geranylgeranyl transferase I-β (GGTI-β) and Geranylgeranyl transferase II-β (GGTII-β) was significantly higher in a subset of OC cell lines. The ectopic expression of TP53 variants in Skov-3 cells, which lack endogenous p53 protein, led to significantly increased expression of HMGCR, GGTI-β, GGTII-β and Farnesyltransferase-β (FT-β) enzymes compared to cells transfected with vector. The inhibition of the pre-existing mutations in TP53 encoding R248Q in Ovcar-3 cell line significantly decreased p53 protein and also HMGCR, GGTI-β, GGTII-β and FT-β mRNA.
These data suggest that TP53 mutations play critical role in regulation of the activity of MP enzymes, providing a rationale for the evaluation of the pathway inhibitors such as statins and bisphosphonates in the treatment of OC.
Clinical trial identification
Legal entity responsible for the study
The study was designed by AR and MIA, the experimental work was conducted by MIA and MNA.
Higher Committee for Education Development in Iraq (MIA ref D-11-296).
All authors have declared no conflicts of interest.