title: Critical role of prostate apoptosis response-4 in determining the sensitivity of pancreatic cancer cells to small-molecule inhibitor-induced apoptosis.
abstract: Role of prostate apoptosis response-4 (PAR-4) has been well described in prostate cancer. However, its significance in other cancers has not been fully elucidated. For the current study, we selected four pancreatic cancer cell lines (BxPC-3, Colo-357, L3.6pl, and HPAC) that showed differential endogenous expression of PAR-4. We found that nonpeptidic small-molecule inhibitors (SMI) of Bcl-2 family proteins (apogossypolone and TW-37; 250 nmol/L and 1 micromol/L, respectively) could induce PAR-4-dependent inhibition of cell growth and induction of apoptosis. Sensitivity to apoptosis was directly related to the expression levels of PAR-4 (R = 0.92 and R2 = 0.95). Conversely, small interfering RNA against PAR-4 blocked apoptosis, confirming that PAR-4 is a key player in the apoptotic process. PAR-4 nuclear localization is considered a prerequisite for cells to undergo apoptosis, and we found that the treatment of Colo-357 and L3.6pl cells with 250 nmol/L SMI leads to nuclear localization of PAR-4 as confirmed by 4',6-diamidino-2-phenylindole staining. In combination studies with gemcitabine, pretreatment with SMI leads to sensitization of Colo-357 cells to the growth-inhibitory and apoptotic action of a therapeutic drug, gemcitabine. In an in vivo setting, the maximum tolerated dose of TW-37 in xenograft of severe combined immunodeficient mice (40 mg/kg for three i.v. injections) led to significant tumor inhibition. Our results suggest that the observed antitumor activity of SMIs is mediated through a novel pathway involving induction of PAR-4. To our knowledge, this is the first study reporting SMI-mediated apoptosis involving PAR-4 in pancreatic cancer.
authors.affiliation: Department of Pathology, Division of Hematology/Oncology, Wayne State University School of Medicine, Karmanos Cancer Institute, 732 HWCRC, 4100 John R Street, Detroit, MI 48201, USA.
authors.forename: Asfar Sohail
authors.initials: AS
authors.lastname: Azmi
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wang
authors.forename: Ravshan
authors.initials: R
authors.lastname: Burikhanov
authors.forename: Vivek M
authors.initials: VM
authors.lastname: Rangnekar
authors.forename: Guoping
authors.initials: G
authors.lastname: Wang
authors.forename: Jianyong
authors.initials: J
authors.lastname: Chen
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
authors.forename: Fazlul H
authors.initials: FH
authors.lastname: Sarkar
authors.forename: Ramzi M
authors.initials: RM
authors.lastname: Mohammad
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D034741:RNA, Small Interfering; C101296:prostate apoptosis response-4 protein; D003841:Deoxycytidine; D000093542:Gemcitabine
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