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Carcinogenesis Advance Access published online on November 20, 2006
Carcinogenesis, doi:10.1093/carcin/bgl223
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received June 14, 2006
Revised October 31, 2006
Accepted November 6, 2006

CANCER BIOLOGY

Resveratrol induces cell death in colorectal cancer cells by a novel pathway involving lysosomal cathepsin D

Nicol F. Trincheri 1, Giuseppina Nicotra 1, Carlo Follo 1, Roberta Castino 1, and Ciro Isidoro 1 *

1 Laboratorio di Patologia Molecolare, Università del Piemonte Orientale "A. Avogadro", Dipartimento di Scienze Mediche, Novara (Italy)

* To whom correspondence should be addressed.
Ciro Isidoro, E-mail: Isidoro{at}med.unipmn.it


  Abstract

In human colorectal cancer cells the polyphenol resveratrol activated the caspase-dependent intrinsic pathway of apoptosis. This effect was not mediated via estrogen receptors. Pepstatin A, an inhibitor of lysosomal cathepsin D, not E-64d, an inhibitor of cathepsins B and L, prevented resveratrol cytotoxicity. Similar protection was attained by small interference RNA-mediated knock-down of cathepsin D protein expression. Resveratrol promoted the accumulation of mature cathepsin D, induced lysosome leakage and increased cytosolic immunoreactivity of cathepsin D. Inhibition of cathepsin D or its post-transcriptional down-regulation precluded Bax oligomerization, permeabilization of mitochondrial membrane, cytosolic translocation of cytochrome c, caspase 3 activation and TUNEL positivity occurring in resveratrol-treated cells. The present study identifies the lysosome as a novel target of resveratrol activity and demonstrates a hierarchy of the proteolytic pathways involved in its cytotoxic mechanism in which the lysosomal cathepsin D acts upstream the cytosolic caspase activation. Our data indicate that metabolic or pharmacologic or genetic conditions affecting cathepsin D expression and/or activity could reflect on the sensitivity of cancer cells to resveratrol.

Keywords: chemotherapy; lysosomes; mitochondria; apoptosis; caspase.
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