Yue Xuetian, Wang Jianming, Chang Chun-Yuan, Liu Juan, Yang Xue, Zhou Fan, Qiu Xia, Bhatt Vrushank, Guo Jessie Yanxiang, Su Xiaoyang, Zhang Lanjing, Feng Zhaohui, Hu Wenwei
Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA.
Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA.
Cell Death Dis. 2022 Apr 19;13(4):370. doi: 10.1038/s41419-022-04820-x.
LIF, a multifunctional cytokine, is frequently overexpressed in many types of solid tumors, including breast cancer, and plays an important role in promoting tumorigenesis. Currently, how LIF promotes tumorigenesis is not well-understood. Metabolic reprogramming is a hallmark of cancer cells and a key contributor to cancer progression. However, the role of LIF in cancer metabolic reprogramming is unclear. In this study, we found that LIF increases glucose uptake and drives glycolysis, contributing to breast tumorigenesis. Blocking glucose uptake largely abolishes the promoting effect of LIF on breast tumorigenesis. Mechanistically, LIF overexpression enhances glucose uptake via activating the AKT/GLUT1 axis to promote glycolysis. Blocking the AKT signaling by shRNA or its inhibitors greatly inhibits glycolysis driven by LIF and largely abolishes the promoting effect of LIF on breast tumorigenesis. These results demonstrate an important role of LIF overexpression in glucose metabolism reprogramming in breast cancers, which contributes to breast tumorigenesis. This study also reveals an important mechanism underlying metabolic reprogramming of breast cancers, and identifies LIF and its downstream signaling as potential therapeutic targets for breast cancers, especially those with LIF overexpression.
白血病抑制因子（LIF）是一种多功能细胞因子，在包括乳腺癌在内的多种实体瘤中经常过度表达，在促进肿瘤发生中起重要作用。目前，LIF如何促进肿瘤发生尚不清楚。代谢重编程是癌细胞的一个标志，也是癌症进展的关键因素。然而，LIF在癌症代谢重编程中的作用尚不清楚。在本研究中，我们发现LIF增加葡萄糖摄取并驱动糖酵解，促进乳腺肿瘤发生。阻断葡萄糖摄取在很大程度上消除了LIF对乳腺肿瘤发生的促进作用。机制上，LIF过表达通过激活AKT/葡萄糖转运蛋白1（GLUT1）轴增强葡萄糖摄取，从而促进糖酵解。通过短发夹RNA（shRNA）或其抑制剂阻断AKT信号通路可大大抑制LIF驱动的糖酵解，并在很大程度上消除LIF对乳腺肿瘤发生的促进作用。这些结果证明LIF过表达在乳腺癌葡萄糖代谢重编程中起重要作用，这有助于乳腺肿瘤发生。本研究还揭示了乳腺癌代谢重编程的一个重要机制，并确定LIF及其下游信号通路为乳腺癌，尤其是LIF过表达乳腺癌的潜在治疗靶点。
