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 (Tom) Beer, Mushui Dai, Sushant K. Kachhap, Zheng (David) Qian

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Article number4972
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

hypoxia
Androgen Receptors
Androgens
therapy
switches
Switches
glucose
Glucose-6-Phosphate Isomerase
phosphates
Therapeutics
Prostatic Neoplasms
pentose
cancer
glycolysis
deprivation
Pentoses
Enzyme inhibition
homeostasis
Glucose
Pentose Phosphate Pathway

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy. / Geng, Hao; Xue, Changhui; Mendonca, Janet; Sun, Xiao-Xin; Liu, Qiong; Reardon, Patrick N.; Chen, Yingxiao; Qian, Kendrick; Hua, Vivian; Chen, Alice; Pan, Freddy; Yuan, Julia; Dang, Sang; Beer, Tomasz (Tom); Dai, Mushui; Kachhap, Sushant K.; Qian, Zheng (David).

In: Nature Communications, Vol. 9, No. 1, 4972, 01.12.2018.

Research output: Contribution to journalArticle

Geng, H, Xue, C, Mendonca, J, Sun, X-X, Liu, Q, Reardon, PN, Chen, Y, Qian, K, Hua, V, Chen, A, Pan, F, Yuan, J, Dang, S, Beer, TT, Dai, M, Kachhap, SK & Qian, ZD 2018, 'Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy', Nature Communications, vol. 9, no. 1, 4972. https://doi.org/10.1038/s41467-018-07411-7
Geng, Hao ; Xue, Changhui ; Mendonca, Janet ; Sun, Xiao-Xin ; Liu, Qiong ; Reardon, Patrick N. ; Chen, Yingxiao ; Qian, Kendrick ; Hua, Vivian ; Chen, Alice ; Pan, Freddy ; Yuan, Julia ; Dang, Sang ; Beer, Tomasz (Tom) ; Dai, Mushui ; Kachhap, Sushant K. ; Qian, Zheng (David). / Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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