ROS/KRAS/AMPK Signaling Contributes to Gemcitabine-Induced Stem-like Cell Properties in Pancreatic Cancer

Hengqiang Zhao; Shihong Wu; Hehe Li; Qingke Duan; Zhengle Zhang; Qiang Shen; Chunyou Wang; Tao Yin

doi:10.1016/j.omto.2019.07.005

ROS/KRAS/AMPK Signaling Contributes to Gemcitabine-Induced Stem-like Cell Properties in Pancreatic Cancer

Mol Ther Oncolytics. 2019 Aug 9:14:299-312. doi: 10.1016/j.omto.2019.07.005. eCollection 2019 Sep 27.

Authors

Hengqiang Zhao^{1

2}, Shihong Wu^{1

3}, Hehe Li^{1

3}, Qingke Duan^{1

3}, Zhengle Zhang^{1

3}, Qiang Shen⁴, Chunyou Wang^{1

3}, Tao Yin^{1

3}

Affiliations

¹ Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
² Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China.
³ Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 China.
⁴ Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Abstract

Poor prognosis in pancreatic cancer (PanCa) is partially due to chemoresistance to gemcitabine (GEM). Glucose metabolism has been revealed to contribute to the therapeutic resistance and pluripotent state of PanCa cells. However, few studies have focused on the effects of GEM on cancer cell metabolism, stemness of tumor cells, and molecular mechanisms that critically influence PanCa treatment. We demonstrate that GEM treatment induces metabolic reprogramming, reducing mitochondrial oxidation and upregulating aerobic glycolysis, and promotes stem-like behaviors in cancer cells. Inhibiting aerobic glycolysis suppresses cancer cell stemness and strengthens GEM's cytotoxicity. GEM-induced metabolic reprogramming is KRAS dependent, as knockdown of KRAS reverses the metabolic shift. GEM-induced metabolic reprogramming also activates AMP-activated protein kinase (AMPK), which promotes glycolytic flux and cancer stemness. In addition, GEM-induced reactive oxygen species (ROS) activate the KRAS/AMPK pathway. This effect was validated by introducing exogenous hydrogen peroxide (H₂O₂). Taken together, these findings reveal a counterproductive GEM effect during PanCa treatment. Regulating cellular redox, targeting KRAS/AMPK signaling, or reversing metabolic reprogramming might be effective approaches to eliminate cancer stem cells (CSCs) and enhance chemosensitivity to GEM to improve the prognosis of PanCa patients.

Keywords: AMPK; KRAS; ROS; aerobic glycolysis; cancer stem cells; chemotherapy; pancreatic cancer.