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MDA-7/IL-24, a novel tumor suppressor/cytokine is ubiquitinated and regulated by the ubiquitin-proteasome system, and inhibition of MDA-7/IL-24 degradation enhances the antitumor activity Gopalan B; Shanker M; Scott A; Branch CD; Chada S; Ramesh RCancer Gene Ther 2008[Jan]; 15 (1): 1-8Steady-state protein levels are determined by the balance between protein synthesis and degradation. Protein half-lives are determined primarily by degradation, and the major degradation pathways involve either lysosomal destruction or an ATP-dependent process involving ubiquitination to target proteins to the proteosome. Studies have shown that multiple tumor-suppressor proteins are ubiquitinated and degraded by the 26S proteasome. In the present study, we investigated whether the tumor suppressor/cytokine melanoma differentiation-associated gene-7/interleukin-24 gene (MDA-7/IL-24) protein is ubiquitinated and its degradation controlled by the proteasome. Treatment of ovarian (2008) and lung (H1299) tumor cells with adenoviral delivery of mda-7 (Ad-mda7) or Ad-mda7 plus the proteosome inhibitor MG132 showed that MDA-7 protein expression was dependent upon proteosome activity. Western blot and immunoprecipitation analyses verified that the MDA-7 protein was ubiquitinated and that ubiquitinated-MDA-7 levels were increased in MG132-treated cells. These results were confirmed using small interfering RNA (siRNA)-mediated knockdown of ubiquitin. Furthermore, ubiquitinated MDA-7 protein was degraded by the 26S proteasome, as MDA-7 accumulation was observed only when cells were treated with MG132 but not with lysosome or protease inhibitors. Inhibition of the catalytic beta-5 subunit of the 20S proteasome using siRNA resulted in MDA-7 protein accumulation. Finally, treatment of tumor cells with Ad-mda7 plus the proteasome inhibitor bortezomib resulted in increased tumor cell killing. Our results show that MDA-7/IL-24 is ubiquitinated and degraded by the 26S proteasome. Furthermore, inhibition of MDA-7 degradation results in enhanced tumor killing, identifying a novel anticancer strategy.|*Ubiquitination/drug effects/genetics[MESH]|Adenoviridae[MESH]|Boronic Acids/pharmacology[MESH]|Bortezomib[MESH]|Catalytic Domain/genetics[MESH]|Cell Line, Tumor[MESH]|Female[MESH]|Genetic Therapy[MESH]|Humans[MESH]|Interleukins/*biosynthesis/genetics[MESH]|Lung Neoplasms/genetics/*metabolism/therapy[MESH]|Lysosomes/genetics/metabolism[MESH]|Ovarian Neoplasms/genetics/*metabolism/therapy[MESH]|Protease Inhibitors/pharmacology[MESH]|Proteasome Endopeptidase Complex/genetics/*metabolism[MESH]|Proteasome Inhibitors[MESH]|Pyrazines/pharmacology[MESH]|RNA, Small Interfering/biosynthesis/genetics[MESH]|Tumor Suppressor Proteins/*biosynthesis/genetics[MESH]|Ubiquitin/antagonists & inhibitors/genetics/*metabolism[MESH] |
