Mcl-1 protects prostate cancer cells from cell death mediated by chemotherapy-induced DNA damage

Teresita Reiner, Alicia de las Pozas, Ricardo Parrondo, Deanna Palenzuela, William Cayuso, Priyamvada Rai, Carlos Perez-Stable

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

The anti-apoptotic protein Mcl-1 is highly expressed in castration-resistant prostate cancer (CRPC), resulting in resistance to apoptosis and association with poor prognosis. Although predominantly localized in the cytoplasm, there is evidence that Mcl-1 exhibits nuclear localization where it is thought to protect against DNA damage-induced cell death. The role of Mcl-1 in mediating resistance to chemotherapy-induced DNA damage in prostate cancer (PCa) is not known. We show in human PCa cell lines and in TRAMP, a transgenic mouse model of PCa, that the combination of the antimitotic agent ENMD-1198 (analog of 2-methoxyestradiol) with betulinic acid (BA, increases proteotoxic stress) targets Mcl-1 by increasing its proteasomal degradation, resulting in increased γH2AX (DNA damage) and apoptotic/necrotic cell death. Knockdown of Mcl-1 in CRPC cells leads to elevated γH2AX, DNA strand breaks, and cell death after treatment with 1198 + BA- or doxorubicin. Additional knockdowns in PC3 cells suggests that cytoplasmic Mcl-1 protects against DNA damage by blocking the mitochondrial release of apoptosis-inducing factor and thereby preventing its nuclear translocation and subsequent interaction with the cyclophilin A endonuclease. Overall, our results suggest that chemotherapeutic agents that target Mcl-1 will promote cell death in response to DNA damage, particularly in CRPC.

Original languageEnglish (US)
Pages (from-to)703-715
Number of pages13
JournalOncoscience
Volume2
Issue number8
DOIs
StatePublished - 2015

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Keywords

  • Antimitotic
  • Apoptosis
  • DNA damage
  • Necrosis
  • Proteotoxic stress

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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