pp32/PHAPI determines the apoptosis response of non-small-cell lung cancer
pp32/PHAPI determines the apoptosis response of non-small-cell lung cancer
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DOI：
10.1038/sj.cdd.4402256
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发表时间：
2008-01-01
影响因子：
12.4
通讯作者：
Schuler, M.
中科院分区：
文献类型：
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作者：
Hoffarth, S.;Zitzer, A.;Schuler, M.
在恶性转化过程中，癌细胞必须逃避细胞内在的肿瘤抑制机制，包括细胞凋亡，从而获得对临床应用的抗癌疗法相对耐受的表型。凋亡信号转导缺陷的分子特征可能有助于确定预后标志物和开发新的治疗策略。为此，我们对人类非小细胞肺癌（NSCLC）细胞中药物诱导的细胞凋亡进行了功能分析。我们发现，原发性耐药与体外细胞凋亡小体依赖的caspase激活缺陷相关。虽然细胞色素c诱导的溶酶体形成得以维持，但随后的caspase-9和-3活化在耐药NSCLC中被废除。添加重组pp 32/推定的人类HLA II类相关蛋白（pp 32/PHAPI），被描述为前列腺癌中推定的肿瘤抑制因子，成功地恢复了体外缺陷细胞色素c诱导的caspase激活。pp 32/PHAPI的条件性表达在体外和在小鼠肿瘤模型中使NSCLC细胞对凋亡敏感。来自NSCLC患者的肿瘤样本的免疫组织化学分析显示，pp 32/PHAPI的表达与化疗后改善的结果相关。这些结果确定pp 32/PHAPI作为体外和体内癌细胞凋亡反应的调节剂，并作为晚期NSCLC化疗后生存的预测因子。
During malignant transformation, cancer cells have to evade cell-intrinsic tumor suppressor mechanisms including apoptosis, thus acquiring a phenotype that is relatively resistant to clinically applied anticancer therapies. Molecular characterization of apoptotic signal transduction defects may help to identify prognostic markers and to develop novel therapeutic strategies. To this end we have undertaken functional analyses of drug-induced apoptosis in human non-small cell-lung cancer (NSCLC) cells. We found that primary drug resistance correlated with defects in apoptosome-dependent caspase activation in vitro. While cytochrome c-induced apoptosome formation was maintained, the subsequent activation of caspase-9 and-3 was abolished in resistant NSCLC. The addition of recombinant pp32/putative human HLA class II-associated protein (pp32/PHAPI), described as a putative tumor suppressor in prostate cancer, successfully restored defective cytochrome c-induced caspase activation in vitro. Conditional expression of pp32/PHAPI sensitized NSCLC cells to apoptosis in vitro and in a murine tumor model in vivo. Immunohistochemical analyses of tumor samples from NSCLC patients revealed that the expression of pp32/PHAPI correlated with an improved outcome following chemotherapy. These results identify pp32/PHAPI as regulator of the apoptosis response of cancer cells in vitro and in vivo, and as a predictor of survival following chemotherapy for advanced NSCLC.