STAT3:FOXM1 and MCT1 drive uterine cervix carcinoma fitness to a lactate-rich microenvironment

Abstract

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.

Monocarboxylate Transporter 4 Regulates Glioblastoma Motility and Monocyte Binding Ability

“…Previous reports have indicated that STAT3 increases HIF-1α protein stability and interacts with HIF-1α target gene promoters [62]. Other reports have also shown that activation of STAT3 is involved in the modulation of expression of pH-regulating proteins, CA9 and MCT4 [63]. The present study revealed that acetyl-STAT3 was activated in response to hypoxia, and inhibition of STAT3 decreased hypoxia-induced MCT4 and HIF-1α expression ( Figure 6D,E).…”

Monocarboxylate transporter 1 (MCT1), a tool to stratify acute myeloid leukemia (AML) patients and a vehicle to kill cancer cells

“…Monocarboxylate transporters are essential for lactate import and export. In cancer context MCT1 is described as being expressed in cells that preferentially import and consume lactate whereas MCT4 is more prone to export lactate [ 12 ]. Although a report in glycolytic cells from brain tumors has described MCT1 as a mediator of lactate export [ 18 ].…”

“…Metabolic adaptation involves an orchestrated remodelling of metabolic intervenients and in lactate metabolism the most important elements are monocarboxylate transporters (MCTs) [ 9 , 10 ] - in cancer MCT1 and MCT4 seem to be the most relevant [ 11 , 12 , 39 ]; and lactate dehydrogenases (LDH), which are able to convert lactate and pyruvate in both ways and have even been considered as putative therapeutic targets in cancer [ 40 , 41 ]. HL60 reacted to lactate and VEGF by increasing MCT1 levels and THP1 expresses high levels of MCT1, which are maintained upon lactate and VEGF exposure (Figure 3A and 3C ).…”

“…HL60 reacted to lactate and VEGF by increasing MCT1 levels and THP1 expresses high levels of MCT1, which are maintained upon lactate and VEGF exposure (Figure 3A and 3C ). So MCT1 must be pivotal in lactate uptake by cancer cells (as HL60 and THP1) that are able to fully metabolize lactate as described in other cancer models [ 12 , 39 ]. In addition, this is the first time that VEGF is described as a regulator of MCT1 expression.…”

“…The metabolic symbiosis which occurs among cancer cells and between cancer cells and other stromal cells [ 8 ] requires a tightly coordinated system of monocarboxylate transporters (MCTs) [ 9 , 10 ] and lactate dehydrohgenases (LDH) [ 11 ]. MCTs and LDHs allow the production and export of lactate after glycolysis and afterwards the import and its convertion into pyruvate to supply tricarboxylic acid (TCA) cycle and OXPHOS for energy and biomass production [ 12 ]. Accordingly, the increased levels of lactic acidosis in cancer patients can be a consequence not only of cell lysis but also of cell proliferation, in which lactate is transiently secreted and afterwards taken up.…”