PPARγ ligands and ATRA inhibit the invasion of human breast cancer cells in vitro
PPARγ ligands and ATRA inhibit the invasion of human breast cancer cells in vitro
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DOI：
10.1023/a:1023366117157
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发表时间：
2003-05-01
影响因子：
3.8
通讯作者：
Elstner, E
中科院分区：
文献类型：
--
作者：
Liu, H;Zang, C;Elstner, E
侵袭和转移是乳腺癌患者死亡的主要原因。基质金属蛋白酶(MMPs)，尤其是明胶酶(MMP2和MMP9)的高表达与肿瘤的进展密切相关。核激素受体(NHR)之一，过氧化物酶体增殖物激活受体。(PPAR)，是一种配体激活的转录因子，在正常细胞和癌细胞中调节细胞的增殖、分化和凋亡。最近的数据表明，PPAR。其配体的激活还可以抑制明胶酶B(MMP9)，阻断巨噬细胞和肌肉细胞的迁移，这意味着PPAR可能是PPAR。配体可能对肿瘤细胞具有抗侵袭活性。在这项研究中，我们展示了合成的PPAR对高侵袭性的人乳腺癌细胞株MDA-MB-231的治疗作用。在Transwell(R)小室模型中，配体吡格列酮(PGZ)、罗格列酮(RGZ)、GW7845或其天然配体15-脱氧-Delta12，14-前列腺素J(2)(15d-PGJ(2))在体外没有观察到明显的细胞毒性，导致通过重组基底膜(Matrigel(R))显著抑制该细胞的侵袭能力。维甲酸受体(RAR)的配体全反式维甲酸(ATRA)也被研究，并显示出类似的抑制侵袭作用。PPAR刺激后，MMP9的表达无明显变化。这些处理上调了明胶酶天然的组织抑制因子，即基质金属蛋白酶组织抑制因子-1(TIMP-1)，降低了条件培养液中明胶酶的明胶溶解活性。由于在MDA-MB-231细胞的条件培养液中未检测到基质金属蛋白酶-2，并且只有基质金属蛋白酶-9中和抗体降低了条件培养液的明胶溶解活性，因此PPAR很可能降低了明胶溶解活性。配体和/或全反式维甲酸是由于基质金属蛋白酶-9活性降低所致。由于在我们的体外模型中，该细胞系通过Matrigel(R)的迁移是绝对需要的，正如中和抗MMP-2和-9的抗体所证明的那样，我们得出结论，明胶酶活性的下调至少在一定程度上是降低MDA-MB-231细胞系体外侵袭能力的原因。我们的结果首次表明，PPAR。配体可能通过靶向其侵袭行为，对高侵袭性乳腺癌的治疗具有治疗价值。
Invasion and metastasis are the main causes of death in breast cancer patients. Increased expression of matrix metalloproteinases (MMPs), especially gelatinases (MMP- 2 and - 9), has been closely associated with tumor progression. One of the nuclear hormone receptors (NHR), peroxisome proliferator-activated receptor. ( PPAR.), is a ligand-activated transcriptional factor that regulates cell proliferation, differentiation and apoptosis in both normal and cancer cells. Recent data indicate that PPAR. activation by its ligands can also lead to the inhibition of gelatinase B (MMP-9) and the blockage of migration in macrophages and muscle cells, implying the possibility that PPAR. ligands may possess anti-invasive activities on tumor cells. In this study, we showed that treatment of the highly aggressive human breast cancer cell line MDA-MB-231 with the synthetic PPAR. ligands pioglitazone (PGZ), rosiglitazone (RGZ), GW7845 or its natural ligand 15-deoxy-Delta 12, 14-prostaglandin J(2)(15d-PGJ(2)), at concentrations at which no obvious cytotoxicity was observed in vitro, led to a significant inhibition of the invasive capacities of this cell line through a reconstituted basement membrane (Matrigel(R)) in a Transwell(R) chamber model. All-trans-retinoic acid (ATRA), a ligand for retinoic acid receptor (RAR), was also studied and showed a similar inhibitory effect on invasion. Although no change was observed in the expression of MMP- 9 after challenge with PPAR. ligands and/or ATRA on this cell line, the natural tissue inhibitor of gelatinases, namely the tissue inhibitor of MMP 1 (TIMP-1) was upregulated by these treatments and the gelatinolytic activities of gelatinases in the conditioned media were decreased. Since MMP- 2 was not detectable in the conditioned media of MDA-MB-231 cells, and the gelatinolytic activities of the conditioned media were reduced only by MMP- 9 neutralizing antibodies, it is most likely that the reduction of gelatinolytic activities by PPAR. ligands and/or ATRA was due to the decrease of MMP- 9 activities. Because MMP- 9 was absolutely required in the transmigration of this cell line through Matrigel(R) in our in vitro model as demonstrated by neutralizing antibodies against MMP- 2 and - 9, we concluded that down-regulation of gelatinase activities is, at least in part, responsible for the reduction of the invasive capacities of MDA-MB-231 cell line in vitro. Our results, for the first time, indicate that PPAR. ligands may have therapeutic value for the treatment of highly invasive breast cancer by targeting its invasive behavior.