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Tumor Biology

, Volume 35, Issue 10, pp 10213–10221 | Cite as

MLN2238 synergizes BH3 mimetic ABT-263 in castration-resistant prostate cancer cells by induction of NOXA

  • Xinghua Wei
  • Ping Zhou
  • Xuanting Lin
  • Yurong Lin
  • Sifeng Wu
  • Pengfei Diao
  • Haiqing Xie
  • Keji Xie
  • Ping Tang
Research Article

Abstract

Patients undergoing androgen blockade therapy develop castration-resistant prostate cancer (CRPC), which is associated with Bcl-2 upregulation and results in disease progression and death. In recent years, promising therapeutic agents, such as the BH3-only mimetic ABT-263 and proteasome inhibitors, have been developed and widely evaluated against a broad spectrum of cancer types, including prostate cancer, alone or in combination with other chemotherapeutic agents. In this study, the antitumor efficacy of ABT-263 and MLN2238 were evaluated as single agents and in combination in four CRPC cell lines: PC3, C4-2B, C4-2, and DU145. The viability of the treated cells and markers of apoptosis were assayed. Protein-protein interactions were analyzed by co-immunoprecipitation in drug-treated cells. Lentivirus-mediated short hairpin RNA was used to knockdown Bax, Mcl-1, and NOXA expressions. We found that ABT-263 and MLN2238 alone exhibited a mild cytotoxicity, and in combination, they elicited a synergistic cytotoxic effect in CRPC cells. The cell apoptosis induced by the combination drug treatment was evidenced by enhanced caspase-3 and Poly (ADP-ribose) polymerase (PARP) cleavage, and annexin-V-positive staining was significantly depleted by Bax knockdown. MLN2238 treatment upregulated NOXA and Mcl-1 expression, leading NOXA/Mcl-1 complexes to disassociate Bak from its complexes with Mcl-1 and enhancing ABT263-triggered Bax activation. NOXA knockdown by short hairpin RNA significantly attenuated the cytotoxicity of ABT-263 and MLN2238 co-administration. In conclusion, MLN2238 and ABT-263 synergistically triggered apoptosis in CRPC cells by upregulating NOXA and activating Bax, indicating a promising therapeutic strategy for the treatment of CRPC.

Keywords

Castration-resistant prostate cancer ABT-263 MLN2238 NOXA Mcl-1 

Abbreviations

ADT

Androgen deprivation therapy

CI

Combination index

CRPC

Castration-resistant prostate cancer

MOMP

Mitochondrial outer membrane permeabilization

Notes

Acknowledgments

This work was supported by the National Natural Science Foundation Grant of China (No. 81072091/H1619) and Key Project of Guangzhou Municipal Health Bureau Grant, China (No. 20121A021006) to Ping Tang.

Conflict of interest

None

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Xinghua Wei
    • 1
  • Ping Zhou
    • 2
  • Xuanting Lin
    • 1
  • Yurong Lin
    • 1
  • Sifeng Wu
    • 1
  • Pengfei Diao
    • 1
  • Haiqing Xie
    • 1
  • Keji Xie
    • 1
  • Ping Tang
    • 1
  1. 1.Department of UrologyGuangzhou First People’s Hospital, Guangzhou Medical UniversityGuangzhouChina
  2. 2.Department of PathophysiologyGuangzhou Medical UniversityGuangzhouChina

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