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N-Myc promotes therapeutic resistance development of neuroendocrine prostate cancer by differentially regulating miR-421/ATM pathway.

Publication ,  Journal Article
Yin, Y; Xu, L; Chang, Y; Zeng, T; Chen, X; Wang, A; Groth, J; Foo, W-C; Liang, C; Hu, H; Huang, J
Published in: Mol Cancer
January 18, 2019

BACKGROUND: MYCN amplification or N-Myc overexpression is found in approximately 40% NEPC and up to 20% CRPC patients. N-Myc has been demonstrated to drive disease progression and hormonal therapeutic resistance of NEPC/CRPC. Here, we aim to identify the molecular mechanisms underlying the N-Myc-driven therapeutic resistance and provide new therapeutic targets for those N-Myc overexpressed NEPC/CRPC. METHODS: N-Myc overexpressing stable cell lines for LNCaP and C4-2 were generated by lentivirus infection. ADT-induced senescence was measured by SA-β-gal staining in LNCaP cells in vitro and in LNCaP xenograft tumors in vivo. Migration, cell proliferation and colony formation assays were used to measure the cellular response after overexpressing N-Myc or perturbing the miR-421/ATM pathway. CRISPR-Cas9 was used to knock out ATM in C4-2 cells and MTS cell viability assay was used to evaluate the drug sensitivity of N-Myc overexpressing C4-2 cells in response to Enzalutamide and ATM inhibitor Ku60019 respectively or in combination. RESULTS: N-Myc overexpression suppressed ATM expression through upregulating miR-421 in LNCaP cells. This suppression alleviated the ADT-induced senescence in vitro and in vivo. Surprisingly, N-Myc overexpression upregulated ATM expression in C4-2 cells and this upregulation promoted migration and invasion of prostate cancer cells. Further, the N-Myc-induced ATM upregulation in C4-2 cells rendered the cells resistance to Enzalutamide, and inhibition of ATM by CRISPR-Cas9 knockout or ATM inhibitor Ku60019 re-sensitized them to Enzalutamide. CONCLUSIONS: N-Myc differentially regulating miR-421/ATM pathway contributes to ADT resistance and Enzalutamide resistance development respectively. Combination treatment with ATM inhibitor re-sensitizes N-Myc overexpressed CRPC cells to Enzalutamide. Our findings would offer a potential combination therapeutic strategy using ATM kinase inhibitor and Enzalutamide for the treatment of a subset of mCRPC with N-Myc overexpression that accounts for up to 20% CRPC patients.

Duke Scholars

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Published In

Mol Cancer

DOI

EISSN

1476-4598

Publication Date

January 18, 2019

Volume

18

Issue

1

Start / End Page

11

Location

England

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Up-Regulation
  • Thioxanthenes
  • Signal Transduction
  • Protein Kinase Inhibitors
  • Prostatic Neoplasms, Castration-Resistant
  • Phenylthiohydantoin
  • Oncology & Carcinogenesis
  • Nitriles
  • N-Myc Proto-Oncogene Protein
 

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Yin, Y., Xu, L., Chang, Y., Zeng, T., Chen, X., Wang, A., … Huang, J. (2019). N-Myc promotes therapeutic resistance development of neuroendocrine prostate cancer by differentially regulating miR-421/ATM pathway. Mol Cancer, 18(1), 11. https://doi.org/10.1186/s12943-019-0941-2
Yin, Yu, Lingfan Xu, Yan Chang, Tao Zeng, Xufeng Chen, Aifeng Wang, Jeff Groth, et al. “N-Myc promotes therapeutic resistance development of neuroendocrine prostate cancer by differentially regulating miR-421/ATM pathway.Mol Cancer 18, no. 1 (January 18, 2019): 11. https://doi.org/10.1186/s12943-019-0941-2.
Yin, Yu, et al. “N-Myc promotes therapeutic resistance development of neuroendocrine prostate cancer by differentially regulating miR-421/ATM pathway.Mol Cancer, vol. 18, no. 1, Jan. 2019, p. 11. Pubmed, doi:10.1186/s12943-019-0941-2.
Yin Y, Xu L, Chang Y, Zeng T, Chen X, Wang A, Groth J, Foo W-C, Liang C, Hu H, Huang J. N-Myc promotes therapeutic resistance development of neuroendocrine prostate cancer by differentially regulating miR-421/ATM pathway. Mol Cancer. 2019 Jan 18;18(1):11.
Journal cover image

Published In

Mol Cancer

DOI

EISSN

1476-4598

Publication Date

January 18, 2019

Volume

18

Issue

1

Start / End Page

11

Location

England

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Up-Regulation
  • Thioxanthenes
  • Signal Transduction
  • Protein Kinase Inhibitors
  • Prostatic Neoplasms, Castration-Resistant
  • Phenylthiohydantoin
  • Oncology & Carcinogenesis
  • Nitriles
  • N-Myc Proto-Oncogene Protein