Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy

Hao Geng, Changhui Xue, Janet Mendonca, Xiao-Xin Sun, Qiong Liu, Patrick N. Reardon, Yingxiao Chen, Kendrick Qian, Vivian Hua, Alice Chen, Freddy Pan, Julia Yuan, Sang Dang, Tomasz M. Beer, Mu-Shui Dai, Sushant K. Kachhap and David Z. Qian ()
Additional contact information
Hao Geng: Oregon Health & Science University
Changhui Xue: Oregon Health & Science University
Janet Mendonca: Johns Hopkins Kimmel Cancer Center
Xiao-Xin Sun: Oregon Health & Science University
Qiong Liu: Oregon Health & Science University
Patrick N. Reardon: NMR Core facility, Oregon State University
Yingxiao Chen: Oregon Health & Science University
Kendrick Qian: Oregon Health & Science University
Vivian Hua: Oregon Health & Science University
Alice Chen: Oregon Health & Science University
Freddy Pan: Oregon Health & Science University
Julia Yuan: Oregon Health & Science University
Sang Dang: Oregon Health & Science University
Tomasz M. Beer: Oregon Health & Science University
Mu-Shui Dai: Oregon Health & Science University
Sushant K. Kachhap: Johns Hopkins Kimmel Cancer Center
David Z. Qian: Oregon Health & Science University

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract Despite recent advances, the efficacy of androgen/androgen receptor (AR)-targeted therapy remains limited for many patients with metastatic prostate cancer. This is in part because prostate cancers adaptively switch to the androgen/AR-independent pathway for survival and growth, thereby conferring therapy resistance. Tumor hypoxia is considered as a major cause of treatment resistance. However, the exact mechanism is largely unclear. Here we report that chronic-androgen deprivation therapy (ADT) in the condition of hypoxia induces adaptive androgen/AR-independence, and therefore confers resistance to androgen/AR-targeted therapy, e.g., enzalutamide. Mechanistically, this is mediated by glucose-6-phosphate isomerase (GPI), which is transcriptionally repressed by AR in hypoxia, but restored and increased by AR inhibition. In turn, GPI maintains glucose metabolism and energy homeostasis in hypoxia by redirecting the glucose flux from androgen/AR-dependent pentose phosphate pathway (PPP) to hypoxia-induced glycolysis pathway, thereby reducing the growth inhibitory effect of enzalutamide. Inhibiting GPI overcomes the therapy resistance in hypoxia in vitro and increases enzalutamide efficacy in vivo.

Date: 2018
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DOI: 10.1038/s41467-018-07411-7

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