Ueda Haruka, Ishiguro Tatsuya, Mori Yutaro, Yamawaki Kaoru, Okamoto Koji, Enomoto Takayuki, Yoshihara Kosuke
Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Advanced Comprehensive Research Organization, Teikyo University, Tokyo, Japan.
Cell Death Discov. 2024 Oct 11;10(1):435. doi: 10.1038/s41420-024-02204-y.
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. In this study, we present variations in sensitivities to a PI3K-Akt-mTORC1 inhibitor among in vitro endometrial cancer stem cell-enriched spheroid cells from clinical specimens. The in vitro sensitivity was consistent with the effects observed in in vivo spheroid-derived xenograft tumor models. Our findings revealed a complementary suppressive effect on endometrial cancer spheroid cell growth with the combined use of aldehyde dehydrogenase (ALDH) and PI3K-Akt inhibitors. In the PI3K-Akt-mTORC1 signaling cascade, the influence of ALDH on mTORC1 was partially channeled through retinoic acid-induced lactate dehydrogenase A (LDHA) activation. LDHA inhibition was found to reduce endometrial cancer cell growth, aligning with the effects of mTORC1 inhibition. Building upon our previous findings highlighting ALDH-driven glycolysis through GLUT1 in uterine endometrial cancer spheroid cells, curbing mTORC1 enhanced 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 interaction between mTORC1 and ALDH-influenced glycolysis holds promise for developing novel strategies to combat this aggressive cancer.
癌症干细胞与恶性肿瘤的侵袭性表型相关。子宫内膜癌的一个显著特征是PI3K-Akt-mTOR通路的激活。在本研究中，我们展示了来自临床标本的体外富集子宫内膜癌干细胞的球状体细胞对PI3K-Akt-mTORC1抑制剂的敏感性差异。体外敏感性与在体内球状体衍生的异种移植肿瘤模型中观察到的效果一致。我们的研究结果揭示了醛脱氢酶（ALDH）和PI3K-Akt抑制剂联合使用对子宫内膜癌球状体细胞生长具有互补抑制作用。在PI3K-Akt-mTORC1信号级联反应中，ALDH对mTORC1的影响部分通过视黄酸诱导的乳酸脱氢酶A（LDHA）激活来传导。发现抑制LDHA可减少子宫内膜癌细胞的生长，这与抑制mTORC1的效果一致。基于我们之前的研究结果，即突出了ALDH通过子宫子宫内膜癌球状体细胞中的GLUT1驱动糖酵解，抑制mTORC1可通过激活GLUT1增强葡萄糖转运。值得注意的是，LDHA表达升高与不良临床生存和肿瘤分级升高相关，尤其是在晚期。总的来说，我们的研究结果强调了ALDH-LDHA-mTORC1级联反应在子宫内膜癌增殖中的关键作用。针对mTORC1与ALDH影响的糖酵解之间的相互作用，有望开发出对抗这种侵袭性癌症的新策略。
