Regulation of FANCD2 by the mTOR pathway contributes to the resistance of cancer cells to DNA double-strand breaks

Changxian Shen, Duane Oswald, Doris Phelps, Hakan Cam, Christopher E. Pelloski, Qishen Pang, Peter J Houghton

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Deregulation of the mTOR pathway is closely associated with tumorigenesis. Accordingly, mTOR inhibitors such as rapamycin and mTOR-selective kinase inhibitors have been tested as cancer therapeutic agents. Inhibition of mTOR results in sensitization to DNA-damaging agents; however, the molecular mechanism is not well understood. We found that an mTOR-selective kinase inhibitor, AZD8055, significantly enhanced sensitivity of a pediatric rhabdomyosarcoma xenograft to radiotherapy and sensitized rhabdomyosarcoma cells to the DNA interstrand cross-linker (ICL) melphalan. Sensitization correlated with drug-induced downregulation of a key component of the Fanconi anemia pathway, FANCD2 through mTOR regulation of FANCD2 gene transcripts via mTORC1-S6K1. Importantly, we show that FANCD2 is required for the proper activation of ATM-Chk2 checkpoint in response to ICL and that mTOR signaling promotes ICL-induced ATM-Chk2 checkpoint activation by sustaining FANCD2. In FANCD2-deficient lymphoblasts, FANCD2 is essential to suppress endogenous and induced DNA damage, and FANCD2-deficient cells showed impaired ATM-Chk2 and ATR-Chk1 activation, which was rescued by reintroduction of wild-type FANCD2. Pharmacologic inhibition of PI3K-mTOR-AKT pathway in Rh30 rhabdomyosarcoma cells attenuated ICL-induced activation of ATM, accompanied with the decrease of FANCD2. These data suggest that the mTOR pathway may promote the repair of DNA double-strand breaks by sustaining FANCD2 and provide a novel mechanism of how the Fanconi anemia pathway modulates DNA damage response and repair.

Original languageEnglish (US)
Pages (from-to)3393-3401
Number of pages9
JournalCancer Research
Volume73
Issue number11
DOIs
StatePublished - Jun 1 2013
Externally publishedYes

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Double-Stranded DNA Breaks
Rhabdomyosarcoma
Fanconi Anemia
DNA Damage
Phosphotransferases
Neoplasms
Melphalan
DNA
Sirolimus
Phosphatidylinositol 3-Kinases
Heterografts
DNA Repair
Carcinogenesis
Radiotherapy
Down-Regulation
Pediatrics
Pharmaceutical Preparations
Genes
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Regulation of FANCD2 by the mTOR pathway contributes to the resistance of cancer cells to DNA double-strand breaks. / Shen, Changxian; Oswald, Duane; Phelps, Doris; Cam, Hakan; Pelloski, Christopher E.; Pang, Qishen; Houghton, Peter J.

In: Cancer Research, Vol. 73, No. 11, 01.06.2013, p. 3393-3401.

Research output: Contribution to journalArticle

Shen, Changxian ; Oswald, Duane ; Phelps, Doris ; Cam, Hakan ; Pelloski, Christopher E. ; Pang, Qishen ; Houghton, Peter J. / Regulation of FANCD2 by the mTOR pathway contributes to the resistance of cancer cells to DNA double-strand breaks. In: Cancer Research. 2013 ; Vol. 73, No. 11. pp. 3393-3401.
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