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ATM deficiency promotes progression of CRPC by enhancing Warburg effect.

Publication ,  Journal Article
Xu, L; Ma, E; Zeng, T; Zhao, R; Tao, Y; Chen, X; Groth, J; Liang, C; Hu, H; Huang, J
Published in: Endocr Relat Cancer
January 1, 2019

ATM is a well-known master regulator of double strand break (DSB) DNA repair and the defective DNA repair has been therapeutically exploited to develop PARP inhibitors based on the synthetic lethality strategy. ATM mutation is found with increased prevalence in advanced metastatic castration-resistant prostate cancer (mCRPC). However, the molecular mechanisms underlying ATM mutation-driving disease progression are still largely unknown. Here, we report that ATM mutation contributes to the CRPC progression through a metabolic rather than DNA repair mechanism. We showed that ATM deficiency generated by CRISPR/Cas9 editing promoted CRPC cell proliferation and xenograft tumor growth. ATM deficiency altered cellular metabolism and enhanced Warburg effect in CRPC cells. We demonstrated that ATM deficiency shunted the glucose flux to aerobic glycolysis by upregulating LDHA expression, which generated more lactate and produced less mitochondrial ROS to promote CRPC cell growth. Inhibition of LDHA by siRNA or inhibitor FX11 generated less lactate and accumulated more ROS in ATM-deficient CRPC cells and therefore potentiated the cell death of ATM-deficient CRPC cells. These findings suggest a new therapeutic strategy for ATM-mutant CRPC patients by targeting LDHA-mediated glycolysis metabolism, which might be effective for the PARP inhibitor resistant mCRPC tumors.

Duke Scholars

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Published In

Endocr Relat Cancer

DOI

EISSN

1479-6821

Publication Date

January 1, 2019

Volume

26

Issue

1

Start / End Page

59 / 71

Location

England

Related Subject Headings

  • Prostatic Neoplasms, Castration-Resistant
  • Oncology & Carcinogenesis
  • Naphthalenes
  • Mice
  • Male
  • Lactic Acid
  • L-Lactate Dehydrogenase
  • Humans
  • Glucose
  • Disease Progression
 

Citation

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Xu, L., Ma, E., Zeng, T., Zhao, R., Tao, Y., Chen, X., … Huang, J. (2019). ATM deficiency promotes progression of CRPC by enhancing Warburg effect. Endocr Relat Cancer, 26(1), 59–71. https://doi.org/10.1530/ERC-18-0196
Xu, Lingfan, Enze Ma, Tao Zeng, Ruya Zhao, Yulei Tao, Xufeng Chen, Jeff Groth, Chaozhao Liang, Hailiang Hu, and Jiaoti Huang. “ATM deficiency promotes progression of CRPC by enhancing Warburg effect.Endocr Relat Cancer 26, no. 1 (January 1, 2019): 59–71. https://doi.org/10.1530/ERC-18-0196.
Xu L, Ma E, Zeng T, Zhao R, Tao Y, Chen X, et al. ATM deficiency promotes progression of CRPC by enhancing Warburg effect. Endocr Relat Cancer. 2019 Jan 1;26(1):59–71.
Xu, Lingfan, et al. “ATM deficiency promotes progression of CRPC by enhancing Warburg effect.Endocr Relat Cancer, vol. 26, no. 1, Jan. 2019, pp. 59–71. Pubmed, doi:10.1530/ERC-18-0196.
Xu L, Ma E, Zeng T, Zhao R, Tao Y, Chen X, Groth J, Liang C, Hu H, Huang J. ATM deficiency promotes progression of CRPC by enhancing Warburg effect. Endocr Relat Cancer. 2019 Jan 1;26(1):59–71.
Journal cover image

Published In

Endocr Relat Cancer

DOI

EISSN

1479-6821

Publication Date

January 1, 2019

Volume

26

Issue

1

Start / End Page

59 / 71

Location

England

Related Subject Headings

  • Prostatic Neoplasms, Castration-Resistant
  • Oncology & Carcinogenesis
  • Naphthalenes
  • Mice
  • Male
  • Lactic Acid
  • L-Lactate Dehydrogenase
  • Humans
  • Glucose
  • Disease Progression