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

Chander Peddaboina, Daniel Jupiter, Steven Fletcher, Jeremy L. Yap, Arun Rai, Richard P. Tobin, Weihua Jiang, Philip Rascoe, M. Karen N Rogers, W. R. Smythe, Xiaobo Cao

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number541
JournalBMC Cancer
Volume12
DOIs
StatePublished - Nov 21 2012
Externally publishedYes

Fingerprint

Down-Regulation
Neoplasms
Western Blotting
Drug Therapy
Survival
Apoptosis
Inhibition (Psychology)
Annexin A5
Ubiquitination
Cell Lineage
RNA Interference
Immunoprecipitation
Colonic Neoplasms
Lung Neoplasms
Colon
Proteins
Immunohistochemistry
Staining and Labeling
Cell Line
Genes

Keywords

  • Bcl-xL
  • Cancer
  • Mcl-1
  • Ubiquitination
  • USP9X

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics

Cite this

The downregulation of Mcl-1 via USP9X inhibition sensitizes solid tumors to Bcl-xl inhibition. / Peddaboina, Chander; Jupiter, Daniel; Fletcher, Steven; Yap, Jeremy L.; Rai, Arun; Tobin, Richard P.; Jiang, Weihua; Rascoe, Philip; Rogers, M. Karen N; Smythe, W. R.; Cao, Xiaobo.

In: BMC Cancer, Vol. 12, 541, 21.11.2012.

Research output: Contribution to journalArticle

Peddaboina, C, Jupiter, D, Fletcher, S, Yap, JL, Rai, A, Tobin, RP, Jiang, W, Rascoe, P, Rogers, MKN, Smythe, WR & Cao, X 2012, 'The downregulation of Mcl-1 via USP9X inhibition sensitizes solid tumors to Bcl-xl inhibition', BMC Cancer, vol. 12, 541. https://doi.org/10.1186/1471-2407-12-541
Peddaboina, Chander ; Jupiter, Daniel ; Fletcher, Steven ; Yap, Jeremy L. ; Rai, Arun ; Tobin, Richard P. ; Jiang, Weihua ; Rascoe, Philip ; Rogers, M. Karen N ; Smythe, W. R. ; Cao, Xiaobo. / The downregulation of Mcl-1 via USP9X inhibition sensitizes solid tumors to Bcl-xl inhibition. In: BMC Cancer. 2012 ; Vol. 12.
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abstract = "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.",
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AU - Jupiter, Daniel

AU - Fletcher, Steven

AU - Yap, Jeremy L.

AU - Rai, Arun

AU - Tobin, Richard P.

AU - Jiang, Weihua

AU - Rascoe, Philip

AU - Rogers, M. Karen N

AU - Smythe, W. R.

AU - Cao, Xiaobo

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