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Rottlerin stimulates apoptosis in pancreatic cancer cells through interactions with proteins of the Bcl-2 family

Ohno, Izumi and Eibl, Guido and Odinkova, Irina and Edderkaoui, Mouad and Damoiseaux, Robert D. and Yazbec, Moussa and Abrol, Ravinder and Goddard, William A., III and Yokosuka, Osamu and Pandol, Stephen J. and Gukovskaya, Anna S. (2010) Rottlerin stimulates apoptosis in pancreatic cancer cells through interactions with proteins of the Bcl-2 family. American Journal of Physiology. Gastrointestinal and Liver Physiology, 298 (1). G63-G73. ISSN 0193-1857. PMCID PMC2806098.

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Rottlerin is a polyphenolic compound derived from Mallotus philipinensis. In the present study, we show that rottlerin decreased tumor size and stimulated apoptosis in an orthotopic model of pancreatic cancer with no effect on normal tissues in vivo. Rottlerin also induced apoptosis in pancreatic cancer (PaCa) cell lines by interacting with mitochondria and stimulating cytochrome c release. Immunoprecipitation results indicated that rottlerin disrupts complexes of prosurvival Bcl-xL with Bim and Puma. Furthermore, siRNA knockdown showed that Bim and Puma are necessary for rottlerin to stimulate apoptosis. We also showed that rottlerin and Bcl-2 and Bcl-xL inhibitor BH3I-2' stimulate apoptosis through a common mechanism. They both directly interact with mitochondria, causing increased cytochrome c release and mitochondrial depolarization, and both decrease sequestration of BH3-only proteins by Bcl-xL. However, the effects of rottlerin and BH3I-2' on the complex formation between Bcl-xL and BH3-only proteins are different. BH3I-2' disrupts complexes of Bcl-xL with Bad but not with Bim or Puma, whereas rottlerin had no effect on the Bcl-xL interaction with Bad. Also BH3I-2', but not rottlerin, required Bad to stimulate apoptosis. In conclusion, our results demonstrate that rottlerin has a potent proapoptotic and antitumor activity in pancreatic cancer, which is mediated by disrupting the interaction between prosurvival Bcl-2 proteins and proapoptotic BH3-only proteins. Thus rottlerin represents a promising novel agent for pancreatic cancer treatment.

Item Type:Article
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URLURL TypeDescription CentralArticle
Abrol, Ravinder0000-0001-7333-6793
Goddard, William A., III0000-0003-0097-5716
Additional Information:© 2010 American Physiological Society. Submitted June 29, 2009 ; accepted in final form September 10, 2009. This study was supported by the Hirshberg Foundation for Pancreatic Cancer Research, the NIH grants CA119025 (to A. Gukovskaya.), NCCAM AT003960 (to S. Pandol), and the Department of Veterans Affairs Merit Award (to A. Gukovskaya).
Funding AgencyGrant Number
Hirshberg Foundation for Pancreatic Cancer ResearchUNSPECIFIED
Department of Veterans AffairsUNSPECIFIED
Subject Keywords:phytochemical; polyphone; mitochondria; proapoptotic protein
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Issue or Number:1
PubMed Central ID:PMC2806098
Record Number:CaltechAUTHORS:20100120-105514079
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Official Citation:Izumi Ohno, Guido Eibl, Irina Odinokova, Mouad Edderkaoui, Robert D. Damoiseaux, Moussa Yazbec, Ravinder Abrol, William A. Goddard, III, Osamu Yokosuka, Stephen J. Pandol, and Anna S. Gukovskaya Rottlerin stimulates apoptosis in pancreatic cancer cells through interactions with proteins of the Bcl-2 family Am J Physiol Gastrointest Liver Physiol 298: G63-G73, 2010. First published doi:10.1152/ajpgi.00257.2009
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:17242
Deposited By: Jason Perez
Deposited On:28 Jan 2010 19:25
Last Modified:03 Oct 2019 01:25

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