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Selective apoptosis induction by the cancer chemopreventive agent N-(4-hydroxyphenyl)retinamide is achieved by modulating mitochondrial bioenergetics in premalignant and malignant human prostate epithelial cells

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Abstract

Prostate tumorigenesis is coupled with an early metabolic switch in transformed prostate epithelial cells that effectively increases their mitochondrial bioenergetic capacity. The synthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) inhibits prostate cancer development in vivo, and triggers reactive oxygen species (ROS)-dependent prostate cancer cell apoptosis in vitro. The possibility that 4HPR-induced ROS production is associated with mitochondrial bioenergetics and required for apoptosis induction in transformed prostate epithelial cells in vitro would advocate a prospective mechanistic basis for 4HPR-mediated prostate cancer chemoprevention in vivo. We investigated this tenet by comparing and contrasting 4HPR’s effects on premalignant PWR-1E and malignant DU-145 human prostate epithelial cells. 4HPR promoted a dose- and/or time-dependent apoptosis induction in PWR-1E and DU-145 cells, which was preceded by and dependent on an increase in mitochondrial ROS production. In this regard, the PWR-1E cells were more sensitive than the DU-145 cells, and they consumed roughly twice as much oxygen as the DU-145 cells suggesting oxidative phosphorylation was higher in the premalignant cells. Interestingly, increasing the [Ca2+] in the culture medium of the PWR-1E cells attenuated their proliferation as well as their mitochondrial bioenergetic capacity and 4HPR’s cytotoxic effects. Correspondingly, the respiration-deficient derivatives (i.e., ρ0 cells lacking mitochondrial DNA) of DU-145 cells were markedly resistant to 4HPR-induced ROS production and apoptosis. Together, these observations implied that the reduction of mitochondrial bioenergetics protected PWR-1E and DU-145 cells against the cytotoxic effects of 4HPR, and support the concept that oxidative phosphorylation is an essential determinant in 4HPR’s apoptogenic signaling in transformed human prostate epithelial cells.

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Abbreviations

4HPR:

N-(4-Hydroxyphenyl)retinamide

DCF:

2′,7′-Dichlorofluorescein

ΔΨm :

Mitochondrial inner transmembrane potential

DiOC6(3):

3,3′-Dihexyloxacarbocyanine iodide

EthBr:

Ethidium bromide

FITC:

Fluorescein isothiocyanate

HQNO:

2-Heptyl-4-hydroxyquinoline-N-oxide

KGM:

Keratinocyte growth medium

Me2SO:

Dimethyl sulfoxide

mtDNA:

Mitochondrial DNA

NAC:

N-Acetyl-l-cysteine

OXPHOS:

Oxidative phosphorylation

PI:

Propidium iodide

ρ0 :

Respiration-deficient cells lacking mtDNA

ROS:

Reactive oxygen species

SELECT:

Selenium and vitamin E cancer prevention trial

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Acknowledgments

This work was supported by the National Institutes of Health (Grant CA133901-01 to Numsen Hail, Jr.) and the University of Colorado Denver School of Pharmacy. The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Colorado Denver School of Pharmacy, C238-P15 Research 2, 12700 E. 19th Avenue, Room 3008, Aurora, CO, 80045, USA

    Numsen Hail Jr., Ping Chen & Jadwiga J. Kepa

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  1. Numsen Hail Jr.
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  2. Ping Chen
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  3. Jadwiga J. Kepa
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Correspondence to Numsen Hail Jr..

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Hail, N., Chen, P. & Kepa, J.J. Selective apoptosis induction by the cancer chemopreventive agent N-(4-hydroxyphenyl)retinamide is achieved by modulating mitochondrial bioenergetics in premalignant and malignant human prostate epithelial cells. Apoptosis 14, 849–863 (2009). https://doi.org/10.1007/s10495-009-0356-4

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