Critical role of prostate apoptosis response-4 in determining the sensitivity of pancreatic cancer cells to small-molecule inhibitor-induced apoptosis.
Critical role of prostate apoptosis response-4 in determining the sensitivity of pancreatic cancer cells to small-molecule inhibitor-induced apoptosis.
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DOI：
10.1158/1535-7163.mct-08-0438
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发表时间：
2008-09
影响因子：
5.7
通讯作者：
Mohammad RM
中科院分区：
文献类型：
--
作者：
Azmi AS;Wang Z;Burikhanov R;Rangnekar VM;Wang G;Chen J;Wang S;Sarkar FH;Mohammad RM
前列腺癌中前列腺细胞凋亡反应-4(PAR-4)的作用已被充分描述。然而，它在其他癌症中的意义还没有完全阐明。在目前的研究中，我们选择了四个胰腺癌细胞株(BxPC-3，COLO-357，L3.6pl和HPAC)，它们显示了PAR-4的内源性表达差异。我们发现Bcl2家族蛋白的非肽性小分子抑制剂(Apoossypolone和TW-37，分别为250nmoL/L和1μ/L)可以诱导PAR-4依赖的细胞生长抑制和诱导细胞凋亡。细胞对凋亡的敏感性与PAR-4的表达水平直接相关(R=0.92，R2=0.95)。相反，针对PAR-4的小干扰RNA阻止了细胞凋亡，证实了PAR-4是细胞凋亡过程中的关键角色。PAR-4的核定位被认为是细胞发生凋亡的先决条件，我们发现250nmol/L SMI处理COLO-357和L3.6pl细胞后，4‘，6-二氨基-2-苯基吲哚染色证实了PAR-4的核定位。在与吉西他滨的联合研究中，SMI的预处理导致Colo-357细胞对治疗药物吉西他滨的生长抑制和凋亡作用敏感。在活体环境中，TW-37在严重联合免疫缺陷小鼠异种移植中的最大耐受量(40 mg/kg，三次静脉注射)。注射)导致显著的肿瘤抑制。我们的结果表明，SMIs的抗肿瘤活性是通过诱导PAR-4的一种新途径介导的。据我们所知，这是第一个报道SMI介导的涉及PAR-4的胰腺癌细胞凋亡的研究。[摩尔癌症治疗2008；7(9)：2884-93]
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 μmol/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 immuno-deficient 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. [Mol Cancer Ther 2008;7(9):2884–93]