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

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Tumor Biology

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.

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Abbreviations

ADT:

Androgen deprivation therapy

CI:

Combination index

CRPC:

Castration-resistant prostate cancer

MOMP:

Mitochondrial outer membrane permeabilization

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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.

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Authors and Affiliations

  1. Department of Urology, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, 510180, China

    Xinghua Wei, Xuanting Lin, Yurong Lin, Sifeng Wu, Pengfei Diao, Haiqing Xie, Keji Xie & Ping Tang

  2. Department of Pathophysiology, Guangzhou Medical University, Guangzhou, 510182, China

    Ping Zhou

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  1. Xinghua Wei
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  2. Ping Zhou
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  3. Xuanting Lin
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Correspondence to Ping Tang.

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Xinghua Wei, Ping Zhou, and Xuanting Lin contributed equally to this work.

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Wei, X., Zhou, P., Lin, X. et al. MLN2238 synergizes BH3 mimetic ABT-263 in castration-resistant prostate cancer cells by induction of NOXA. Tumor Biol. 35, 10213–10221 (2014). https://doi.org/10.1007/s13277-014-2333-y

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  • DOI: https://doi.org/10.1007/s13277-014-2333-y

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