PTEN sensitizes prostate cancer cells to death receptor-mediated and drug-induced apoptosis through a FADD-dependent pathway
PTEN sensitizes prostate cancer cells to death receptor-mediated and drug-induced apoptosis through a FADD-dependent pathway
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DOI：
10.1038/sj.onc.1205054
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发表时间：
2002-01
期刊：
影响因子：
8
通讯作者：
X. Yuan;Y. Whang
中科院分区：
文献类型：
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作者：
X. Yuan;Y. Whang
PTEN肿瘤抑制因子在人类肿瘤中经常发生突变。PTEN功能的丧失与通过磷脂酰肌醇-3激酶/Akt途径的组成性存活信号传导相关。因此，我们想知道PTEN功能的重建是否会导致前列腺癌细胞凋亡抗性的逆转。腺病毒介导的PTEN表达完全抑制了LNCaP前列腺癌细胞中Akt的组成性激活，并增强了由广泛的凋亡刺激诱导的凋亡。PTEN表达使细胞对肿瘤坏死因子、抗Fas抗体和TRAIL诱导的死亡受体介导的凋亡敏感。PTEN还使细胞对由激酶抑制剂星形孢菌素和化疗剂米托蒽醌和依托泊苷诱导的非受体介导的凋亡敏感。PTEN介导的细胞凋亡伴随着caspase-3和caspase-8的激活，并被广泛特异性caspase抑制剂Z-VAD-favor抑制。Bcl-2过表达还可以阻断PTEN介导的细胞凋亡。PTEN的脂质磷酸酶活性是细胞凋亡所必需的，因为选择性缺乏脂质磷酸酶活性的PTEN G129 E突变体不能使细胞对细胞凋亡敏感。PTEN介导的凋亡涉及死亡受体介导的和药物诱导的凋亡的FADD依赖性途径，因为显性负性FADD突变体的共表达阻断了PTEN介导的凋亡。由于在死亡受体信号传导中，FADD介导半胱天冬酶-8的活化，其进而切割BID，并且由于半胱天冬酶-8在PTEN介导的细胞凋亡中被活化，我们检查了PTEN介导的细胞凋亡中的BID切割。在用低剂量的星形孢菌素和米托蒽醌处理后，PTEN促进BID切割。BID切割被显性阴性FADD抑制。总之，这些数据与以下假设一致：PTEN通过FADD依赖性途径促进胱天蛋白酶-8活化和BID裂解来促进药物诱导的细胞凋亡。
The PTEN tumor suppressor is frequently mutated in human tumors. Loss of PTEN function is associated with constitutive survival signaling through the phosphatidylinositol-3 kinase/Akt pathway. Therefore, we asked if reconstitution of PTEN function would lead to the reversal of resistance to apoptosis in prostate cancer cells. Adenovirus-mediated expression of PTEN completely suppressed constitutive Akt activation in LNCaP prostate cancer cells and enhanced apoptosis induced by a broad range of apoptotic stimuli. PTEN expression sensitized cells to death receptor-mediated apoptosis induced by tumor necrosis factor, anti-Fas antibody, and TRAIL. PTEN also sensitized cells to non-receptor mediated apoptosis induced by a kinase inhibitor staurosporine and chemotherapeutic agents mitoxantrone and etoposide. PTEN-mediated apoptosis was accompanied by caspase-3 and caspase-8 activation and was inhibited by a broad specificity caspase inhibitor Z-VAD-fmk. Bcl-2 overexpression also blocked PTEN-mediated apoptosis. Lipid phosphatase activity of PTEN is required for apoptosis as the PTEN G129E mutant selectively deficient in lipid phosphatase activity was unable to sensitize cells to apoptosis. PTEN-mediated apoptosis involves a FADD-dependent pathway for both death receptor-mediated and drug-induced apoptosis as coexpression of a dominant negative FADD mutant blocked PTEN-mediated apoptosis. Since in death receptor signaling, FADD mediates activation of caspase-8, which in turn cleaves BID, and since caspase-8 is activated in PTEN-mediated apoptosis, we examined BID cleavage in PTEN-mediated apoptosis. PTEN facilitated BID cleavage after treatment with low doses of staurosporine and mitoxantrone. BID cleavage was inhibited by dominant negative FADD. Taken together, these data are consistent with the hypothesis that PTEN promotes drug-induced apoptosis by facilitating caspase-8 activation and BID cleavage through a FADD-dependent pathway.