Search

Uterine cervix cancer is the second most common malignancy in women worldwide with human papillomavirus (HPV) as the etiologic factor. The two main histological variants, squamous cell carcinomas (SCC) and adenocarcinomas (AC), resemble the cell morphology of exocervix and endocervix, respectively. Cancer metabolism is a cancer hallmark conditioned by the microenvironment. As uterine cervix homeostasis is dependent on lactate, we hypothesized lactate plays a role in uterine cervix cancer progression. Using in vitro (SiHa-SCC and HeLa-AC) and BALB-c/SCID models, we demonstrated that lactate metabolism is linked to histological types, with SCC predominantly consuming and AC producing lactate. MCT1 is a key factor, allowing lactate consumption and being regulated in vitro by lactate through the FOXM1:STAT3 pathway. In vivo models showed that SCC (SiHa) expresses MCT1 and is dependent on lactate to grow, whereas AC (HeLa) expresses MCT1 and MCT4, with higher growth capacities. Immunohistochemical analysis of tissue microarrays (TMA) from human cervical tumors showed that MCT1 expression associates with the SCC type and metastatic behavior of AC, whereas MCT4 expression concomitantly increases from in situ SCC to invasive SCC and is significantly associated with the AC type. Consistently, FOXM1 expression is statistically associated with MCT1 positivity in SCC, whereas the expression of FOXO3a, a FOXM1 functional antagonist, is linked to MCT1 negativity in AC. Our study reinforces the role of the microenvironment in the metabolic adaptation of cancer cells, showing that cells that retain metabolic features of their normal counterparts are positively selected by the organ's microenvironment and will survive. In particular, MCT1 was shown to be a key element in uterine cervix cancer development; however, further studies are needed to validate MCT1 as a suitable therapeutic target in uterine cervix cancer.

Ovarian cancer is the leading cause of death from gynaecological malignancies due to difficulties in early detection, diagnosis and therapy of the disease. There is an urgent need for testing novel tumour markers and therapeutic agents. Histone deacetylases (HDACs) inhibitors are a new class of target anticancer agents, which block the deacetylation function, inducing cell cycle arrest, differentiation and/or apoptosis. Vorinostat is an inhibitor of class I and II HDACs and butyric acid is a small molecular weight carboxylate that belong to class I HDAC inhibitors. Our aim was to study cell and molecular alterations induced by HDACs inhibitors in ovarian cancer cell lines. Ovarian cancer cell lines used were OV-90 and OVCAR-3 (serous carcinoma), and ES-2 (clear cell carcinoma). Cell lines were exposed to butyric acid and to vorinostat and cell death (apoptosis and necrosis), was evaluated by FACS using Annexin V and 7AAD staining. Notch downstream target genes, and TP53 (mutated in serous carcinomas) and Fibronectin (FN1) genes were evaluated by RQ-PCR. We found that butyric acid was more effective to induce cell death than vorinostat, in all cell lines tested, although Vorinostat was able to induce higher levels of apoptosis in OV-90 than in other cell lines. Regarding the evaluation of Notch pathway, we observed it is activated by butyric acid in all ovarian cell lines, since Notch downstream targets HES1, HEY1 and 2 genes are more expressed after exposure to this compound. TP53 expression is slightly decreased in all cell lines after exposure to butyric acid. Interestingly, FN1 expression decreases in OV90 whereas it increases in ES2 and OVCAR3 after exposure to vorinostat. We conclude that butyric acid induces cell death in all cell lines.