Glycolysis-mTORC1 crosstalk drives rapid proliferation in patient-derived endometrial cancer spheroids with ALDH activity

Abstract

Abstract Cancer stem cells are associated with aggressive phenotypes of malignant tumors. A prominent feature of uterine endometrial cancer is the activation of the PI3K-Akt-mTOR pathway. Herein, we present variations in sensitivities to a PI3K-Akt-mTORC1 inhibitor among in vitro endometrial cancer stem cell-enriched spheroid cells from clinical specimens. Intriguingly, the in vitro sensitivity mirrored effects observed in in vivo spheroid-derived xenograft tumor models. Our findings reveal a complementary suppressive effect on endometrial cancer spheroid cell growth when aldehyde dehydrogenase (ALDH) and PI3K-Akt inhibitors are combined. In the PI3K-Akt-mTORC1 signaling cascade, the influence of ALDH on mTORC1 is partially channeled through retinoic acid-induced lactate dehydrogenase A (LDHA) activation. LDHA inhibition was found to reduce endometrial cancer cell growth, paralleling the effects of mTORC1 inhibition. Building upon our prior findings highlighting ALDH-driven glycolysis through GLUT1 in uterine endometrial cancer spheroid cells, curbing mTORC1 bolstered glucose transport via GLUT1 activation. Notably, elevated LDHA expression correlated with adverse clinical survival and escalated tumor grade, especially in advanced stages. Collectively, our findings emphasize the pivotal role of ALDH-LDHA-mTORC1 cascade in the proliferation of endometrial cancer. Targeting the intricate interplay between mTORC1 and ALDH-influenced glycolysis could pave the way for novel strategies to combat this aggressive cancer.