Critical role of prostate apoptosis response-4 in determining the sensitivity of pancreatic cancer cells to small-molecule inhibitor-induced apoptosis.
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.
Azmi
Asfar Sohail
AS
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.
Wang
Zhiwei
Z
Burikhanov
Ravshan
R
Rangnekar
Vivek M
VM
Wang
Guoping
G
Chen
Jianyong
J
Wang
Shaomeng
S
Sarkar
Fazlul H
FH
Mohammad
Ramzi M
RM
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
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D034741:RNA, Small Interfering; C101296:prostate apoptosis response-4 protein; D003841:Deoxycytidine; D000093542:Gemcitabine
Int J Cancer. 2004 Mar 20;109(2):182-8
14750167
Cancer Res. 2001 Oct 1;61(19):7255-63
11585763
Mol Cell Biol. 2005 Feb;25(3):1146-61
15657440
Cell Growth Differ. 1994 Apr;5(4):457-66
8043520
Pancreas. 1998 Jan;16(1):19-25
9436858
Clin Cancer Res. 2007 Apr 1;13(7):2226-35
17404107
CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96
18287387
J Med Chem. 2006 Oct 19;49(21):6139-42
17034116
Exp Cell Res. 2003 Feb 1;283(1):51-66
12565819
Cancer Res. 2006 Sep 1;66(17):8698-706
16951185
Cancer Res. 2006 Aug 1;66(15):7653-60
16885366
Pharm Res. 2008 Sep;25(9):2117-24
18427961
Cancer Res. 2006 Dec 1;66(23):11348-59
17145881
Pancreas. 2005 Nov;31(4):317-24
16258364
Int J Cancer. 2008 Jan 1;122(1):63-70
17893871
Mol Cancer. 2008 Feb 14;7:20
18275607
J Clin Oncol. 2003 Sep 1;21(17):3296-302
12947065
J Clin Oncol. 1997 Jun;15(6):2403-13
9196156
Mol Cell Biol. 2003 Aug;23(16):5516-25
12897127
CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66
17237035
Mol Cell Biol. 1997 Jul;17(7):3823-32
9199316