Nonclassical Activation of Hedgehog Signaling Enhances Multidrug Resistance and Makes Cancer Cells Refractory to Smoothened-targeting Hedgehog Inhibition
Nonclassical Activation of Hedgehog Signaling Enhances Multidrug Resistance and Makes Cancer Cells Refractory to Smoothened-targeting Hedgehog Inhibition
复制标题
DOI：
10.1074/jbc.m112.432302
复制
发表时间：
2013-04-26
影响因子：
4.8
通讯作者：
Shevde, Lalita A.
中科院分区：
文献类型：
--
作者：
Das, Shamik;Samant, Rajeev S.;Shevde, Lalita A.
Hedgehog（Hh）通路在正常发育中至关重要。然而，据报道，它在许多癌症中上调，并与致瘤性和转移有关。由Hh配体引发的Hh信号传导的经典激活导致Smoothened（SMOH）的激活，并最终激活GLI转录因子。经典的Hh信号传导是自分泌或旁分泌的（涉及肿瘤细胞与其基质/微环境之间的相互作用）。肿瘤环境富含可调节肿瘤细胞行为的炎性细胞因子。在这里，我们第一次表明，Hh通路可以非经典上调的炎症细胞因子，骨桥蛋白（OPN）。OPN启动的Akt-GSK 3 β信号转导介导GLI 1的亚细胞分布和活化，导致上皮间质可塑性和耐药性的调节。有趣的是，SMOH抑制剂环巴胺不能解偶联OPN对Hh信号传导的作用，表明OPN非经典地激活GLI介导的转录。考虑到OPN本身在Hh信号传导时被转录激活的事实，我们目前的研究结果强调了前馈恶性循环的可能性，使得Hh通路可能被来自肿瘤环境的刺激非经典地打开。因此，靶向经典Hh配体介导的Hh信号转导激活的药物可能在其干扰途径功能的能力方面受到损害。
The Hedgehog (Hh) pathway is critical in normal development. However, it has been reported to be up-regulated in numerous cancers and implicated in tumorigenicity and metastasis. Classical activation of Hh signaling initiated by Hh ligands results in activation of Smoothened (SMOH) and culminates in the activation of the GLI transcription factors. Classical Hh signaling is autocrine or paracrine (involving interaction between tumor cells and their stroma/microenvironment). The tumor milieu is rich in inflammatory cytokines that can modulate tumor cell behavior. Here, we show for the first time that the Hh pathway can be nonclassically up-regulated by the inflammatory cytokine, osteopontin (OPN). OPN-initiated Akt-GSK3 beta signaling mediates the subcellular distribution and activation of GLI1 resulting in the modulation of epithelial mesenchymal plasticity and drug resistance. Interestingly, the SMOH inhibitor cyclopamine was unable to uncouple the effects of OPN on Hh signaling, indicating that OPN nonclassically activates GLI-mediated transcription. Given the fact that OPN is itself transcriptionally activated upon Hh signaling, our current findings highlight the possibility of a feedforward vicious cycle such that the Hh pathway might be turned on nonclassically by stimuli from the tumor milieu. Thus, drugs that target the classical Hh ligand-mediated activation of Hh signaling may be compromised in their ability to interfere with the functioning of the pathway.