This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zheng, X. Articles by Rebbaa, A. Search for Related Content PubMed PubMed Citation Articles by Zheng, X. Articles by Rebbaa, A.

Senescence-initiated Reversal of Drug Resistance

Specific Role of Cathepsin L

Children’s Memorial Institute for Education and Research, Children’s Memorial Hospital, ¹ Department of Pediatrics, ² Pathology, and ³ Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Chicago, Illinois

The present study was undertaken to verify whether induction of senescence could be sufficient to reverse drug resistance and, if so, to determine the underlying mechanism(s). Our findings indicated that cotreatment of drug-resistant neuroblastoma cells with doxorubicin, at sublethal concentrations, in combination with the pan-caspase inhibitor, Q-VD-OPH, elicited a strong reduction of cell viability that occurred in a caspase-independent manner. This was accompanied by the appearance of a senescence phenotype, as evidenced by increased p21/WAF1 expression and senescence-associated ß-galactosidase activity. Experiments using specific inhibitors of major cellular proteases other than caspases have shown that inhibition of cathepsin L, but not proteasome or cathepsin B, was responsible for the senescence-initiated reversal of drug resistance. This phenomenon appeared to be general because it was valid for other drugs and drug-resistant cell lines. A nonchemical approach, through cell transfection with cathepsin L small interfering RNA, also strongly reversed drug resistance. Further investigation of the underlying mechanism revealed that cathepsin L inhibition resulted in the alteration of intracellular drug distribution. In addition, in vitro experiments have demonstrated that p21/WAF1 is a substrate for cathepsin L, suggesting that inhibition of this enzyme may result in p21/WAF1 stabilization and its increased accumulation. All together, these findings suggest that cathepsin L inhibition in drug-resistant cells facilitates induction of senescence and reversal of drug resistance. This may represent the basis for a novel function of cathepsin L as a cell survival molecule responsible for initiation of resistance to chemotherapy.

This article has been cited by other articles:

				G. Abboud-Jarrous, R. Atzmon, T. Peretz, C. Palermo, B. B. Gadea, J. A. Joyce, and I. Vlodavsky Cathepsin L Is Responsible for Processing and Activation of Proheparanase through Multiple Cleavages of a Linker Segment J. Biol. Chem., June 27, 2008; 283(26): 18167 - 18176. [Abstract] [Full Text] [PDF]

				V. Probin, Y. Wang, A. Bai, and D. Zhou Busulfan Selectively Induces Cellular Senescence but Not Apoptosis in WI38 Fibroblasts via a p53-Independent but Extracellular Signal-Regulated Kinase-p38 Mitogen-Activated Protein Kinase-Dependent Mechanism J. Pharmacol. Exp. Ther., November 1, 2006; 319(2): 551 - 560. [Abstract] [Full Text] [PDF]

				S. Rastogi, B. Joshi, P. Dasgupta, M. Morris, K. Wright, and S. Chellappan Prohibitin Facilitates Cellular Senescence by Recruiting Specific Corepressors To Inhibit E2F Target Genes. Mol. Cell. Biol., June 1, 2006; 26(11): 4161 - 4171. [Abstract] [Full Text] [PDF]

				Y. A. Bulynko, L. C. Hsing, R. W. Mason, D. J. Tremethick, and S. A. Grigoryev Cathepsin L stabilizes the histone modification landscape on the y chromosome and pericentromeric heterochromatin. Mol. Cell. Biol., June 1, 2006; 26(11): 4172 - 4184. [Abstract] [Full Text] [PDF]

				F. Chu, P. M. Chou, X. Zheng, B. L. Mirkin, and A. Rebbaa Control of Multidrug Resistance Gene mdr1 and Cancer Resistance to Chemotherapy by the Longevity Gene sirt1 Cancer Res., November 15, 2005; 65(22): 10183 - 10187. [Abstract] [Full Text] [PDF]

				J. M. Roth, A. Akalu, A. Zelmanovich, D. Policarpio, B. Ng, S. MacDonald, S. Formenti, L. Liebes, and P. C. Brooks Recombinant {alpha}2(IV)NC1 Domain Inhibits Tumor Cell-Extracellular Matrix Interactions, Induces Cellular Senescence, and Inhibits Tumor Growth in Vivo Am. J. Pathol., March 1, 2005; 166(3): 901 - 911. [Abstract] [Full Text] [PDF]