Liu Zhi-Min, Chen George G, Ng Enders K W, Leung Wai-Keung, Sung Joseph J Y, Chung S C Sydney
Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong.
Oncogene. 2004 Jan 15;23(2):503-13. doi: 10.1038/sj.onc.1207173.
Both heme oxygenase-1 (HO-1) and p21(WAF1/Cip1) (p21) are involved in the pathogenesis of human cancer and their functions are closely associated with apoptosis. However, how these two molecules regulate apoptosis in human gastric cancer is unknown. In this study, we studied how HO-1 and p21 were regulated in two gastric cancer cell lines, MKN-45 with wild p53 and MKN-28 with mutant p53. The cells were treated with hemin and cadmium to induce HO-1. The result showed that HO-1 protein was significantly induced by hemin and cadmium in both cells tested. Following the HO-1 expression, p21 level was also markedly induced. The cells with increased HO-1 and p21 showed obviously resistantance to apoptotic stimuli. The levels of HO-1 and p21 induced were significantly inhibited by p38 mitogen-activated protein kinase (p38 MAPK) inhibitor (SB203580) and extracellular-regulated kinase (ERK) inhibitor (PD098059). Parallel to decreased HO-1 and p21 expression, the kinase inhibitors also significantly attenuated the resistance of the cells to apoptosis. The elevated HO-1 and p21 was further found to be associated with increase activity of the nuclear NF-kappaB and the inhibition of NF-kappaB led to the block of their induction. The elevated HO-1 and p21 were also demonstrated to be related to increased cellular inhibitor of caspase inbitory protein-2 (c-IAP2) and decreased caspapse-3 activity. It was noted that the above changes observed were not different between MKN-45 and MKN-28 cells, suggesting the functions of HO-1 and p21 were irrespective of the status of p53. In conclusion, we demonstrate that the resistance to apoptosis in gastric cancer cells with elevated HO-1 and p21 is independent of p53 status in a p38 MAPK- and ERK-mediated pathway with elevated c-IAP2 and decreased caspase-3 activity and that this pathway is sensitive to the inhibition of NF-kappaB.
血红素加氧酶-1（HO-1）和p21（WAF1/Cip1）（p21）均参与人类癌症的发病机制，且它们的功能与细胞凋亡密切相关。然而，这两种分子如何调节人类胃癌中的细胞凋亡尚不清楚。在本研究中，我们研究了在两种胃癌细胞系中HO-1和p21是如何被调节的，这两种细胞系分别是野生型p53的MKN-45和突变型p53的MKN-28。用血红素和镉处理细胞以诱导HO-1。结果显示，在两种受试细胞中，血红素和镉均能显著诱导HO-1蛋白表达。随着HO-1表达增加，p21水平也明显升高。HO-1和p21水平升高的细胞对凋亡刺激表现出明显的抗性。p38丝裂原活化蛋白激酶（p38 MAPK）抑制剂（SB203580）和细胞外调节激酶（ERK）抑制剂（PD098059）能显著抑制诱导产生的HO-1和p21水平。与HO-1和p21表达降低同时，激酶抑制剂也显著减弱了细胞对凋亡的抗性。进一步发现，HO-1和p21水平升高与核NF-κB活性增加相关，而抑制NF-κB会导致其诱导受阻。HO-1和p21水平升高还被证明与细胞凋亡抑制蛋白-2（c-IAP2）活性增加和caspase-3活性降低有关。值得注意的是，在MKN-45和MKN-28细胞中观察到的上述变化并无差异，这表明HO-1和p21的功能与p53状态无关。总之，我们证明，HO-1和p21水平升高的胃癌细胞对凋亡的抗性在p38 MAPK和ERK介导的通路中独立于p53状态，该通路中c-IAP2升高且caspase-3活性降低，并且该通路对NF-κB抑制敏感。
