Interferon-gamma-induced dephosphorylation of STAT3 and apoptosis are dependent on the mTOR pathway
Interferon-gamma-induced dephosphorylation of STAT3 and apoptosis are dependent on the mTOR pathway
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DOI：
10.1016/j.yexcr.2005.12.011
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发表时间：
2006-05-01
影响因子：
3.7
通讯作者：
Rosenfeld, RG
中科院分区：
文献类型：
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作者：
Fang, P;Hwa, V;Rosenfeld, RG
干扰素-γ具有多种生物活性，包括控制细胞生长和抑制肿瘤。在此，我们报道了用干扰素-γ处理人转移性前列腺癌M12细胞株后，细胞增殖受到明显抑制，并诱导了细胞凋亡。这些效应在干扰素-α或干扰素-β中都看不到。M12细胞和许多其他人类癌细胞一样，含有结构性激活的信号转导和转录激活因子3(STAT3)。在M12细胞中，Akt和ERK1/2磷酸化的基础水平也显著升高。值得注意的是，干扰素-γ诱导的M12细胞的凋亡和生长抑制与结构性酪氨酸磷酸化的STAT3(Py-STAT3)的持续抑制有关。然而，当mTOR通路被雷帕霉素特异性阻断时，干扰素-γ诱导的Py-STAT3去磷酸化被抑制。小剂量LY294002抑制PI-3K或PD98059抑制MAPK也抑制mTOR/p70 S6K通路，并与阻断干扰素-γ诱导的Py-STAT3去磷酸化有关。同时，LY294002、PD98OS9或雷帕霉素可阻断干扰素-γ诱导的M12细胞凋亡。然而，抑制mTOR途径并不影响干扰素-γ诱导的STAT1途径的激活，siRNA抑制STAT1的表达也不影响干扰素-γ诱导的Py-STAT3的去磷酸化。综上所述，这些结果表明，完整的mTOR通路对于干扰素-γ诱导的Py-STAT3抑制和细胞凋亡至关重要。因此，我们的研究对经典的JAK/STAT1通路以外的信号通路在干扰素-γ的抗增殖和促凋亡作用中的作用提供了新的见解。(C)2005 Elsevier Inc.保留所有权利。
Interferon-gamma (IFN-gamma) exhibits diverse biological activities, including control of cell growth and tumor suppression. Here, we report that the treatment of M12 cells, a human metastatic prostate cancer cell line, with IFN-gamma, resulted in marked inhibition of cell proliferation and induced apoptosis. These effects were not seen with either IFN-alpha or IFN-beta. M12 cells, like many other human cancer cells, contain constitutively activated signal transducer and activator of transcription 3 (STAT3). The basal levels of both Akt and ERK1/2 phosphorylation are also markedly elevated in M12 cells. Strikingly, IFN-gamma-induced apoptosis and growth inhibition of M12 cells were associated with persistent suppression of the constitutive tyrosine-phosphorylated STAT3 (pY-STAT3). The IFN-gamma-induced dephosphorylation of pY-STAT3, however, was inhibited when the mTOR pathway was specifically blocked by rapamycin. inhibition of PI-3K with low-dose LY294002, or MAPK with PD98059 also suppressed the mTOR/p70 S6k pathway, and correlated with the blockage of IFN-gamma-induced dephosphorylation of pY-STAT3. Simultaneously, treatment with LY294002, PD98OS9, or rapamycin abolished IFN-gamma-induced apoptosis in M12 cells. The inhibition of the mTOR pathway, however, did not affect IFN-gamma-induced activation of STAT1 pathway, and suppression of STAT1 expression by siRNA had no effect on IFN-gamma-induced dephosphorylation of pY-STAT3. Taken together, these results demonstrate that an intact mTOR pathway is critical for IFN-gamma-induced suppression of pY-STAT3 and apoptosis. Our study thus provides novel insights into the contributions of signaling pathways other than the classical JAK/STAT1 pathway in the anti-proliferative, proapoptotic actions of IFN-gamma. (c) 2005 Elsevier Inc. All rights reserved.