The downregulation of Mcl-1 via USP9X inhibition sensitizes solid tumors to Bcl-xl inhibition

BMC Cancer

Chander Peddaboina²  Daniel Jupiter²  Steven Fletcher³  Jeremy L Yap³  Arun Rai¹  Richard P Tobin²  Weihua Jiang²  Philip Rascoe²  M Karen Newell Rogers²  W Roy Smythe²  Xiaobo Cao² 

[1] Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA

[2] Department of Surgery, Scott & White Memorial Hospital and Clinic, The Texas A&M University System, Health Science Center, College of Medicine, Temple, TX 76504, USA

[3] Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA

关键词: Cancer;    Ubiquitination;    USP9X;    Bcl-xL;    Mcl-1;   

Others  :  1080070
DOI  :  10.1186/1471-2407-12-541

 received in 2012-03-23, accepted in 2012-11-12,  发布年份 2012

【 摘 要 】

Background

It has been shown in many solid tumors that the overexpression of the pro-survival Bcl-2 family members Bcl-xL and Mcl-1 confers resistance to a variety of chemotherapeutic agents. Mcl-1 is a critical survival protein in a variety of cell lineages and is critically regulated via ubiquitination.

Methods

The Mcl-1, Bcl-xL and USP9X expression patterns in human lung and colon adenocarcinomas were evaluated via immunohistochemistry. Interaction between USP9X and Mcl-1 was demonstrated by immunoprecipitation-western blotting. The protein expression profiles of Mcl-1, Bcl-xL and USP9X in multiple cancer cell lines were determined by western blotting. Annexin-V staining and cleaved PARP western blotting were used to assay for apoptosis. The cellular toxicities after various treatments were measured via the XTT assay.

Results

In our current analysis of colon and lung cancer samples, we demonstrate that Mcl-1 and Bcl-xL are overexpressed and also co-exist in many tumors and that the expression levels of both genes correlate with the clinical staging. The downregulation of Mcl-1 or Bcl-xL via RNAi was found to increase the sensitivity of the tumor cells to chemotherapy. Furthermore, our analyses revealed that USP9X expression correlates with that of Mcl-1 in human cancer tissue samples. We additionally found that the USP9X inhibitor WP1130 promotes Mcl-1 degradation and increases tumor cell sensitivity to chemotherapies. Moreover, the combination of WP1130 and ABT-737, a well-documented Bcl-xL inhibitor, demonstrated a chemotherapeutic synergy and promoted apoptosis in different tumor cells.

Conclusion

Mcl-1, Bcl-xL and USP9X overexpression are tumor survival mechanisms protective against chemotherapy. USP9X inhibition increases tumor cell sensitivity to various chemotherapeutic agents including Bcl-2/Bcl-xL inhibitors.

【 授权许可】

   
2012 Peddaboina et al.; licensee BioMed Central Ltd.

【 图 表 】

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