Yuan Xiu-Juan, Whang Young E
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, NC 27599-7295, USA.
Oncogene. 2002 Jan 10;21(2):319-27. doi: 10.1038/sj.onc.1205054.
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.
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途径的组成型生存信号传导相关。因此，我们询问PTEN功能的重建是否会导致前列腺癌细胞对凋亡的抗性逆转。腺病毒介导的PTEN表达完全抑制了LNCaP前列腺癌细胞中组成型Akt的激活，并增强了多种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还使细胞对激酶抑制剂星形孢菌素以及化疗药物米托蒽醌和依托泊苷诱导的非受体介导的凋亡敏感。PTEN介导的凋亡伴随着caspase-3和caspase-8的激活，并被广谱特异性caspase抑制剂Z-VAD-fmk抑制。Bcl-2的过表达也阻断了PTEN介导的凋亡。PTEN的脂质磷酸酶活性对于凋亡是必需的，因为选择性缺乏脂质磷酸酶活性的PTEN G129E突变体无法使细胞对凋亡敏感。PTEN介导的凋亡涉及死亡受体介导的凋亡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caspase-8的激活，而caspase-8又反过来切割BID，并且由于caspase-8在PTEN介导的凋亡中被激活，我们研究了PTEN介导的凋亡中BID的切割。用低剂量的星形孢菌素和米托蒽醌处理后，PTEN促进了BID的切割。BID的切割被显性负性FADD抑制。综上所述，这些数据与以下假设一致，即PTEN通过促进caspase-8的激活和通过FADD依赖性途径切割BID来促进药物诱导的凋亡。
