Carcinogenesis Advance Access originally published online on November 20, 2006
Carcinogenesis 2007 28(5):922-931; doi:10.1093/carcin/bgl223
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Resveratrol induces cell death in colorectal cancer cells by a novel pathway involving lysosomal cathepsin D
Laboratorio di Patologia Molecolare, Dipartimento di Scienze Mediche, Università del Piemonte Orientale ‘A. Avogadro’, Via Solaroli 17, 28100 Novara, Italy
* To whom correspondence should be addressed. Tel: +39 0 321 660607; Fax: +39 0 321 620421;Email: Isidoro{at}med.unipmn.it
In human colorectal cancer cells, the polyphenol resveratrol (RV) activated the caspase-dependent intrinsic pathway of apoptosis. This effect was not mediated via estrogen receptors. Pepstatin A, an inhibitor of lysosomal cathepsin D (CD), not (2S,3S)-trans-epoxysuccinyl-L-leucylamido-3-methylbutane ethyl ester, an inhibitor of cathepsins B and L, prevented RV cytotoxicity. Similar protection was attained by small interference RNA-mediated knockdown of CD protein expression. RV promoted the accumulation of mature CD, induced lysosome leakage and increased cytosolic immunoreactivity of CD. Inhibition of CD or its post-transcriptional down-regulation precluded Bax oligomerization, permeabilization of mitochondrial membrane, cytosolic translocation of cytochrome c, caspase 3 activation and terminal deoxinucleotidyl transferase-mediated dUTP-biotin nick end labeling positivity occurring in RV-treated cells. The present study identifies the lysosome as a novel target of RV activity and demonstrates a hierarchy of the proteolytic pathways involved in its cytotoxic mechanism in which the lysosomal CD acts upstream of the cytosolic caspase activation. Our data indicate that metabolic, pharmacologic or genetic conditions affecting CD expression and/or activity could reflect on the sensitivity of cancer cells to RV.
Abbreviations: CB, cathepsin B; CD, cathepsin D; CL, cathepsin L; E64d, (2S,3S)-trans-epoxysuccinyl-L-leucylamido-3-methylbutane ethyl ester; ER, estrogen receptor; FITC, fluorescein isothiocyanate; PBS, phosphate-buffered saline; Pst, pepstatin A; RV, resveratrol; siRNA, small interference RNA; TUNEL, terminal deoxinucleotidyl transferase-mediated dUTP-biotin nick end labeling; ZVAD-fmk, benzyloxycarbonyl-Val-Ala-Asp
Received June 14, 2006; revised October 31, 2006; accepted November 6, 2006.
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