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

• Published in: Tumor biology Vol. 35; no. 10; pp. 10213 - 10221
• Main Authors: Wei, Xinghua, Zhou, Ping, Lin, Xuanting, Lin, Yurong, Wu, Sifeng, Diao, Pengfei, Xie, Haiqing, Xie, Keji, Tang, Ping
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.10.2014; Springer Nature B.V
• Subjects: Aniline Compounds - pharmacology; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis - drug effects; BH3 Interacting Domain Death Agonist Protein - agonists; Biomedical and Life Sciences; Biomedicine; Boron Compounds - pharmacology; Cancer Research; Cell Line, Tumor; Cell Survival - drug effects; Cells; Cytotoxicity; Drug resistance; Drug Synergism; Glycine - analogs & derivatives; Glycine - pharmacology; Humans; Immunoblotting; Immunoprecipitation; Male; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - metabolism; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Research Article; RNA, Small Interfering; Sulfonamides - pharmacology; Transfection; Castration-resistant prostate cancer; Mcl-1; ABT-263; MLN2238; NOXA
• ISSN: 1010-4283; 1423-0380; 1423-0380
• DOI: 10.1007/s13277-014-2333-y

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.