PPARγ inhibitors reduce tubulin protein levels by a PPARγ, PPARδ and proteasome-independent mechanism, resulting in cell cycle arrest, apoptosis and reduced metastasis of colorectal carcinoma cells
PPARγ inhibitors reduce tubulin protein levels by a PPARγ, PPARδ and proteasome-independent mechanism, resulting in cell cycle arrest, apoptosis and reduced metastasis of colorectal carcinoma cells
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DOI：
10.1002/ijc.22361
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发表时间：
2007-02-01
影响因子：
6.4
通讯作者：
Saubermann, Lawrence J.
中科院分区：
文献类型：
--
作者：
Schaefer, Katherine L.;Takahashi, Hirokazu;Saubermann, Lawrence J.
核转录因子过氧化物酶体增殖物激活受体-γ（PPAR γ）已被确定为结肠直肠癌（CRC）小鼠模型中的重要治疗靶点。为了检查PPAR γ抑制剂是否对晚期CRC具有治疗作用，在CRC细胞系和小鼠CRC模型中检查了PPAR γ抑制剂对CRC细胞存活的影响。低剂量（0.1-1 μ M）的PPAR γ抑制剂（T0070907、GW 9662和BADGE）不影响细胞存活，而高剂量（10-100 μ M）的所有3种PPAR γ抑制剂在HT-29、Caco-2和LoVo CRC细胞系中引起半胱天冬酶依赖性凋亡。细胞凋亡之前细胞形态发生改变，并且这种改变不能通过半胱天冬酶抑制来阻止。PPAR-gamma抑制剂也引起G和M细胞周期双阻滞，这不是细胞凋亡或形态学改变所必需的。此外，PPAR-gamma抑制剂引发微管网络的损失。值得注意的是，与其他标准抗微管剂不同，PPAR γ抑制剂通过转录后调节微管蛋白而不是通过改变微管聚合或动力学来引起微管损失。环氧霉素抑制蛋白酶体不能阻止微管蛋白的丢失。siRNA介导的PPARgamma和PPARdelta蛋白的减少没有复制PPARgamma抑制剂的作用或干扰抑制剂对细胞凋亡、细胞周期或微管蛋白的作用。在体外试验中，PPARgamma抑制剂还减少了CRC细胞的迁移和侵袭，并减少了HT-29/SCID CRC异种移植转移模型中转移瘤的数量和大小。这些结果表明，PPAR γ抑制剂是一种新的潜在的抗微管治疗CRC的直接减少微管前体的行为。(c)2006 Wiley-Liss，Inc.
The nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPAR gamma) has been identified as an important therapeutic target in murine models of colorectal cancer (CRC). To examine whether PPAR gamma inhibition has therapeutic effects in late-stage CRC, the effects of PPAR gamma inhibitors on CRC cell survival were examined in CRC cell lines and a murine CRC model. Low doses (0.1-1 mu M) of PPAR gamma inhibitors (T0070907, GW9662 and BADGE) did not affect cell survival, while higher doses (10-100 mu M) of all 3 PPAR gamma inhibitors caused caspase-dependent apoptosis in HT-29, Caco-2 and LoVo CRC cell lines. Apoptosis was preceded by altered cell morphology, and this alteration was not prevented by caspase inhibition. PPAR gamma inhibitors also caused dual G and M cell cycle arrest, which was not required for apoptosis or for morphologic alterations. Furthermore, PPAR gamma inhibitors triggered loss of the microtubule network. Notably, unlike other standard antimicrotubule agents, PPAR gamma inhibitors caused microtubule loss by regulating tubulin post-transcriptionally rather than by altering microtubule polymerization or dynamics. Proteasome inhibition by epoxomicin was unable to prevent tubulin loss. siRNA-mediated reduction of PPAR gamma and PPAR delta proteins did not replicate the effects of PPAR gamma inhibitors or interfere with the inhibitors' effects on apoptosis, cell cycle or tubulin. PPAR gamma inhibitors also reduced CRC cell migration and invasion in assays in vitro and reduced both the number and size of metastases in a HT-29/SCID xenograft metastatic model of CRC. These results suggest that PPAR gamma inhibitors are a novel potential antimicrotubule therapy for CRC that acts by directly reducing microtubule precursors. (c) 2006 Wiley-Liss, Inc.