Carcinogenesis Advance Access published online on November 28, 2007
Carcinogenesis, doi:10.1093/carcin/bgm271
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Resveratrol-induced Apoptosis Depends on the Lipid Kinase Activity of Vps34 and on the Formation of Autophagolysosomes
Laboratorio di Patologia Molecolare, Università del Piemonte Orientale "A. Avogadro", Dipartimento di Scienze Mediche, Novara (Italy)
1 corresponding author: Università del Piemonte Orientale "A. Avogadro", Dipartimento di Scienze Mediche, Via Solaroli 17, 28100 Novara, Tel + 39 (0)321 660607; fax +39 (0)321620421 e-mail: isidoro{at}med.unipmn.it
In human colorectal DLD1 cancer cells, the dietary bioflavonoid Resveratrol (RV) rapidly induced autophagy. This effect was reversible (on removal of the drug), and was associated with increased expression and cytosolic redistribution of the proteins Beclin1 and LC3 II. Supplementing the cells with asparagine abrogated the Beclin-dependent autophagy. When applied acutely (2 h), RV was not toxic, however reiterate chronic (48 h) exposure to RV eventually led to annexin V- and TUNEL-positive cell death. This toxic effect was autophagy-dependent, as it was prevented either by asparagine, by expressing a dominant negative lipid kinase-deficient class III PI3k or by RNA-interference knock-down of Beclin1. Lamp2b silencing abolished the fusion of autophagosomes with lysosomes and preserved cell viability despite the ongoing formation of autophagosomes in cells chronically exposed to RV. The pan-caspase inhibitor ZVAD-fmk inhibited RV-induced cell death, but not autophagy. These results uncover a novel pathway of RV cytotoxicity in which autophagy plays a dual role: (i) at first, it acts as a pro-survival stress response and (ii) at a later time, it switches to a caspase-dependent apoptosis pathway. The present data also indicate that genetic or epigenetic inactivation of autophagy proteins in cancer cells may confer resistance to RV-mediated killing.
Key Words: apoptosis • chemotherapy • lysosomes • autophagy • colorectal cancer • oncosuppressor • asparagine • class III PI3k • Lamp2b • Beclin1
Received July 26, 2007; revised November 20, 2007; accepted November 21, 2007.
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