title: Mcl-1 protects prostate cancer cells from cell death mediated by chemotherapy-induced DNA damage.
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.
authors.affiliation: Geriatric Research, Education, and Clinical Center and Research Service, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL, USA.
authors.forename: Teresita
authors.initials: T
authors.lastname: Reiner
authors.affiliation: Geriatric Research, Education, and Clinical Center and Research Service, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL, USA ; Division of Gerontology & Geriatric Medicine, Department of Medicine, University of Miami Miller School of Medicine, Miami FL, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: de Las Pozas
authors.affiliation: Geriatric Research, Education, and Clinical Center and Research Service, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL, USA.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Parrondo
authors.affiliation: Geriatric Research, Education, and Clinical Center and Research Service, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL, USA.
authors.forename: Deanna
authors.initials: D
authors.lastname: Palenzuela
authors.affiliation: Division of Gerontology & Geriatric Medicine, Department of Medicine, University of Miami Miller School of Medicine, Miami FL, USA.
authors.forename: William
authors.initials: W
authors.lastname: Cayuso
authors.affiliation: Geriatric Research, Education, and Clinical Center and Research Service, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL, USA ; Division of Gerontology & Geriatric Medicine, Department of Medicine, University of Miami Miller School of Medicine, Miami FL, USA ; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami FL, USA.
authors.forename: Priyamvada
authors.initials: P
authors.lastname: Rai
authors.affiliation: Geriatric Research, Education, and Clinical Center and Research Service, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL, USA ; Division of Gerontology & Geriatric Medicine, Department of Medicine, University of Miami Miller School of Medicine, Miami FL, USA ; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami FL, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Perez-Stable
keywords: DNA damage; antimitotic; apoptosis; necrosis; proteotoxic stress