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Blood, 12 February 2009, Vol. 113, No. 7, pp. 1513-1521.
Prepublished online as a Blood First Edition Paper on November 18, 2008; DOI 10.1182/blood-2008-05-157040.
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Submitted May 16, 2008
Accepted October 20, 2008
Targeting PKC: A novel role for beta-catenin in ER stress and apoptotic signaling
Marc S. Raab*, Iris Breitkreutz, Giovanni Tonon, Jing Zhang, Patrick J Hayden, Thu Nguyen, Johannes H Fruehauf, Boris K Lin, Dharminder Chauhan, Teru Hideshima, Nikhil C. Munshi, Kenneth C Anderson, and Klaus Podar
LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States
Center for Applied Cancer Science, Department of Medical Oncology, Dana-Farber Cancer Insitute, Harvard Medical School, Boston, MA, United States
Skip Ackerman Center for Molecular Therapeutics, Division of Gastroenterology, Beth Israel Medical Center, Harvard Medical School, Boston, MA, United States
Eli Lilly and Company, Indianapolis, IN, United States
* Corresponding author; email: marc_raab{at}dfci.harvard.edu.
Targeting protein kinase C (PKC) isoforms by the small molecule inhibitor enzastaurin has shown promising pre-clinical activity in a wide range of tumor cells. In this study, we further delineated its mechanism of action in multiple myeloma (MM) cells and found a novel role of  -catenin in regulating growth and survival of tumor cells. Specifically, inhibition of PKC leads to rapid accumulation of -catenin by preventing the phosphorylation required for its proteasomal degradation. Microarray analysis and siRNA-mediated gene silencing in MM cells revealed that accumulated -catenin activates early ER stress signaling via eIF2 , CHOP and p21, leading to immediate growth inhibition. Furthermore, accumulated -catenin contributes to enzastaurin-induced cell death. Both sequential knock-down of -catenin, c-Jun, and p73, as well as overexpression of -catenin or p73 confirmed that accumulated -catenin triggers c-Jun-dependent induction of p73, thereby conferring MM cell apoptosis. In summary, our data reveal a novel role of -catenin in ER stress-mediated growth inhibition, and a new pro-apoptotic mechanism triggered by -catenin upon inhibition of PKC isoforms. Moreover, we identify p73 as a potential novel therapeutic target in MM. Based on these and previous data, enzastaurin is currently under clinical investigation in a variety of hematologic malignancies including MM.
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