The SGK3-Catalase antioxidant signaling axis drives cervical cancer growth and therapy resistance
Min Wang,
Jiannan Liu,
Xingming Liao,
Yasong Yi,
Yijue Xue,
Ling Yang,
Hailing Cheng,
Pixu Liu
Affiliations
Min Wang
Cancer Institute, The Second Hospital of Dalian Medical University, Dalian Key Laboratory of Molecular Targeted Cancer Therapy, Dalian, China
Jiannan Liu
Cancer Institute, The Second Hospital of Dalian Medical University, Dalian Key Laboratory of Molecular Targeted Cancer Therapy, Dalian, China
Xingming Liao
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning Province, China
Yasong Yi
Cancer Institute, The Second Hospital of Dalian Medical University, Dalian Key Laboratory of Molecular Targeted Cancer Therapy, Dalian, China
Yijue Xue
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning Province, China
Ling Yang
School of Pharmacy, Zunyi Medical University, Zunyi, China; Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China; Department of Pharmacology, Key Laboratory of Basic Pharmacology of Guizhou Province, Zunyi Medical University, Zunyi, China; Corresponding author. School of Pharmacy, Zunyi Medical University, Zunyi, China.
Hailing Cheng
Cancer Institute, The Second Hospital of Dalian Medical University, Dalian Key Laboratory of Molecular Targeted Cancer Therapy, Dalian, China; Corresponding author.
Pixu Liu
Cancer Institute, The Second Hospital of Dalian Medical University, Dalian Key Laboratory of Molecular Targeted Cancer Therapy, Dalian, China; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning Province, China; Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Corresponding author. Cancer Institute, The Second Hospital of Dalian Medical University, Dalian Key Laboratory of Molecular Targeted Cancer Therapy, Dalian, China.
Cancer cells frequently exhibit aberrant redox homeostasis and adaptation to oxidative stress. Hence abrogation of redox adaptation in cancer cells can be exploited for therapeutic benefit. Here we report SGK3 functions as an anti-oxidative factor to promote cell growth and drug resistance in cervical cancers harboring PIK3CA helical domain mutations. Mechanistically, SGK3 is activated upon oxidative stress and exerts anti-ROS activity by stabilizing and activating the antioxidant enzyme catalase. SGK3 interacts with and phosphorylates catalase, promoting its tetrameric state and activity. Meanwhile, SGK3 phosphorylates GSK3β and protects catalase from GSK3β-β-TrCP mediated ubiquitination and proteasomal degradation. Furthermore, SGK3 inhibition not only potentiates CDK4/6 inhibitor Palbociclib-mediated cytotoxicity, but also overcomes cisplatin resistance through ROS-mediated mechanisms. These data uncover the role of SGK3 in maintaining redox homeostasis and suggest that the SGK3-catalase antioxidant signaling axis may be therapeutically targeted to improve treatment efficacy for cervical cancers carrying PIK3CA helical domain mutations.
