Published OnlineFirst January 13, 2012; DOI: 10.1158/1078-0432.CCR-11-2764
Clinical Cancer Research
Letter to the Editor
Targeting Proteasomal Protein Degradation in Cancer–Letter William K.K. Wu
In the recently published Molecular Pathways article (1), Molineaux summarized the recent progress in the development of proteasome inhibitors for the treatment of cancer. The author stated that inhibition of NF-kB is one of the major mechanisms mediating the antitumor effect of proteasome inhibition. This notion has been supported by the finding that proteasome is responsible for the degradation of IkB, which is a major inhibitor of the NF-kB signaling pathway (2). It is therefore believed that proteasome inhibition would lead to the accumulation of IkB and thereby block the NF-kB signaling. However, this concept has recently been challenged. Dolcet and colleagues first reported that the U.S. Food and Drug Administration (FDA)–approved proteasome inhibitor bortezomib activates constitutive NF-kB in endometrial Author's Affiliation: Institute of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong Corresponding Author: William K. K. Wu, The Chinese University of Hong Kong, 701 LKS Medical Sciences Building, Prince of Wales Hospital, Shatin, NT, Hong Kong. Phone: 852-3763-6103; Fax: 852-2144-5330; E-mail:
[email protected] doi: 10.1158/1078-0432.CCR-11-2764 2012 American Association for Cancer Research.
carcinoma cell line (3). Markovina and colleagues also showed that the proteasome inhibitor fails to inhibit constitutive NF-kB activity in myeloma cell lines (4). Hideshima and colleagues later showed that bortezomib and another proteasome inhibitor (lactacystin) promote nonproteasomal degradation of IkB through activation of IKKb and RIP2, resulting in enhanced NF-kB DNA binding in human multiple myeloma cell lines and primary tumor samples (5). Li and colleagues further showed that bortezomib may induce Ikb degradation through calpain activation, which lead to increased p65 (a NF-kB subunit) nuclear translocation and NF-kB activity (6). Above all, pharmacologic inhibition of IKKb or calpain enhances the cytotoxic effect of bortezomib (5, 6). Collectively, these findings suggest that proteasome inhibitor may paradoxically induce NF-kB activation, which serves as an autoregulatory prosurvival mechanism to counteract the cytotoxicity of proteasome inhibition. Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed. Received October 27, 2011; accepted October 31, 2011; published OnlineFirst January 13, 2012.
References 1. Molineaux SM. Molecular pathways: targeting proteasomal protein degradation in cancer. Clin Cancer Res 2012;18:15–20. 2. Palombella VJ, Rando OJ, Goldberg AL, Maniatis T. The ubiquitinproteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell 1994;78:773–85. 3. Dolcet X, Llobet D, Encinas M, Pallares J, Cabero A, Schoenenberger JA, et al. Proteasome inhibitors induce death but activate NF-kappaB on endometrial carcinoma cell lines and primary culture explants. J Biol Chem 2006;281:22118–30.
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4. Markovina S, Callander NS, O'Connor SL, Kim J, Werndli JE, Raschko M, et al. Bortezomib-resistant nuclear factor-kappaB activity in multiple myeloma cells. Mol Cancer Res 2008;6:1356–64. 5. Hideshima T, Ikeda H, Chauhan D, Okawa Y, Raje N, Podar K, et al. Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells. Blood 2009;114:1046–52. 6. Li C, Chen S, Yue P, Deng X, Lonial S, Khuri FR, et al. Proteasome inhibitor PS-341 (bortezomib) induces calpain-dependent IkappaB (alpha) degradation. J Biol Chem 2010;285:16096–104.
Clin Cancer Res; 18(3) February 1, 2012
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Published OnlineFirst January 13, 2012; DOI: 10.1158/1078-0432.CCR-11-2764
Targeting Proteasomal Protein Degradation in Cancer−Letter William K.K. Wu Clin Cancer Res 2012;18:912. Published OnlineFirst January 13, 2012.
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