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A glutaminase isoform switch drives therapeutic resistance and disease progression of prostate cancer.

Publication ,  Journal Article
Xu, L; Yin, Y; Li, Y; Chen, X; Chang, Y; Zhang, H; Liu, J; Beasley, J; McCaw, P; Zhang, H; Young, S; Groth, J; Wang, Q; Locasale, JW; He, Y ...
Published in: Proc Natl Acad Sci U S A
March 30, 2021

Cellular metabolism in cancer is significantly altered to support the uncontrolled tumor growth. How metabolic alterations contribute to hormonal therapy resistance and disease progression in prostate cancer (PCa) remains poorly understood. Here we report a glutaminase isoform switch mechanism that mediates the initial therapeutic effect but eventual failure of hormonal therapy of PCa. Androgen deprivation therapy inhibits the expression of kidney-type glutaminase (KGA), a splicing isoform of glutaminase 1 (GLS1) up-regulated by androgen receptor (AR), to achieve therapeutic effect by suppressing glutaminolysis. Eventually the tumor cells switch to the expression of glutaminase C (GAC), an androgen-independent GLS1 isoform with more potent enzymatic activity, under the androgen-deprived condition. This switch leads to increased glutamine utilization, hyperproliferation, and aggressive behavior of tumor cells. Pharmacological inhibition or RNA interference of GAC shows better treatment effect for castration-resistant PCa than for hormone-sensitive PCa in vitro and in vivo. In summary, we have identified a metabolic function of AR action in PCa and discovered that the GLS1 isoform switch is one of the key mechanisms in therapeutic resistance and disease progression.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

March 30, 2021

Volume

118

Issue

13

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tissue Array Analysis
  • Receptors, Androgen
  • Prostatic Neoplasms
  • Prostate
  • Mice
  • Male
  • Isoenzymes
  • Humans
  • Glutamine
 

Citation

APA
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MLA
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Xu, L., Yin, Y., Li, Y., Chen, X., Chang, Y., Zhang, H., … Huang, J. (2021). A glutaminase isoform switch drives therapeutic resistance and disease progression of prostate cancer. Proc Natl Acad Sci U S A, 118(13). https://doi.org/10.1073/pnas.2012748118
Xu, Lingfan, Yu Yin, Yanjing Li, Xufeng Chen, Yan Chang, Hong Zhang, Juan Liu, et al. “A glutaminase isoform switch drives therapeutic resistance and disease progression of prostate cancer.Proc Natl Acad Sci U S A 118, no. 13 (March 30, 2021). https://doi.org/10.1073/pnas.2012748118.
Xu L, Yin Y, Li Y, Chen X, Chang Y, Zhang H, et al. A glutaminase isoform switch drives therapeutic resistance and disease progression of prostate cancer. Proc Natl Acad Sci U S A. 2021 Mar 30;118(13).
Xu, Lingfan, et al. “A glutaminase isoform switch drives therapeutic resistance and disease progression of prostate cancer.Proc Natl Acad Sci U S A, vol. 118, no. 13, Mar. 2021. Pubmed, doi:10.1073/pnas.2012748118.
Xu L, Yin Y, Li Y, Chen X, Chang Y, Zhang H, Liu J, Beasley J, McCaw P, Young S, Groth J, Wang Q, Locasale JW, Gao X, Tang DG, Dong X, He Y, George D, Hu H, Huang J. A glutaminase isoform switch drives therapeutic resistance and disease progression of prostate cancer. Proc Natl Acad Sci U S A. 2021 Mar 30;118(13).
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

March 30, 2021

Volume

118

Issue

13

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tissue Array Analysis
  • Receptors, Androgen
  • Prostatic Neoplasms
  • Prostate
  • Mice
  • Male
  • Isoenzymes
  • Humans
  • Glutamine