Altered fatty acid oxidation via CPT1A promotes epithelial-to-mesenchymal transition in ovarian cancer.

Abstract

Metabolic alterations are increasingly recognized as fundamental features of cancer. Recent studies have highlighted the involvement of altered fatty acid oxidation (FAO) at different stages of tumor development. As the rate-limiting enzyme of FAO, CPT1 plays a crucial role in these metabolic adaptations in cancer cells. However, the regulation of CPT1 expression and activity in tumor cells still requires detailed investigation. Our studies reveal that CPT1A, a variant of CPT1, is significantly upregulated in ovarian cancer (OC) and correlates with poor prognosis. Inhibition of CPT1A, either by siRNA-mediated knockdown or by etomoxir, reduces the migratory and invasive properties of the OC cells. CPT1A exerts these effects by modulating the expression of epithelial-to-mesenchymal transition (EMT)-associated genes at transcriptional and protein levels. Growth factors such as transforming growth factor beta (TGFβ) are abundant in the tumor microenvironment and modulate the metabolic profile of tumors, thereby promoting EMT. Our findings demonstrate that TGFβ treatment increases the rate of FAO in ovarian cancer cells. Mechanistically, TGFβ mediates this effect by enhancing CPT1A expression and its enzymatic activity in OC cells through an AMPK-dependent pathway. Additionally, we identified NRF2 as a potential transcriptional regulator of CPT1A within the context of TGFβ-AMPK signaling. Finally, inhibiting CPT1A successfully attenuates TGFβ-induced EMT in ovarian cancer cells. Cumulatively, our study underscores the role of CPT1A-mediated FAO in facilitating ovarian cancer progression through TGFβ-induced EMT.