p21-activated kinase 1 determines stem-like phenotype and sunitinib resistance via NF-κB/IL-6 activation in renal cell carcinoma.
p21-activated kinase 1 determines stem-like phenotype and sunitinib resistance via NF-κB/IL-6 activation in renal cell carcinoma.
复制标题
p21 激活激酶 1 通过肾细胞癌中 NF-kappaB/IL-6 激活来确定干细胞样表型和舒尼替尼耐药性。
DOI：
10.1038/cddis.2015.2
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发表时间：
2015-02-12
影响因子：
9
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Zhu Y;Liu H;Xu L;An H;Liu W;Liu Y;Lin Z;Xu J
P21激活的蛋白1(PAK1)是一种丝氨酸/苏氨酸激酶，调节细胞骨架重塑和细胞运动，是多种致癌信号通路的下游节点，可促进细胞增殖、调节细胞凋亡和加速有丝分裂异常，从而导致肿瘤的形成和侵袭。虽然PAK1的表达和活性在多种人类恶性肿瘤中都已被检测到，但其在肾癌(RCC)中潜在的生物学和临床意义仍不清楚。在这项研究中，我们发现肿瘤组织中PAK1和磷酸化PAK1的水平随着TNM分期的进展而增加。升高的磷酸化PAK1水平与进展性特征相关，并表明作为肾癌患者独立不良预后指标的不良总生存期(OS)。此外，在PAK1激酶被特异的PAK1 shRNA、死亡激酶突变体K299R或变构抑制剂IPA3灭活后，PAK1激酶的激活促进了肾癌细胞的生长、集落形成、迁移、侵袭和干细胞样表型，反之亦然。PAK1 shRNA、PAK1突变体K299R和IPA3可改善因增强PAK1激酶活性而给予舒尼替尼的干细胞样表型。此外，核因子-κB(核因子-κB)/白介素6(IL-6)的激活与舒尼替尼治疗后PAK1介导的干性表型有关。IL-6中和抗体和IPA3均增强了舒尼替尼在体内外对肾癌细胞生长的抑制作用。我们的结果揭示，PAK1的致癌激活通过激活NF-κB/IL-6在肾癌中定义了维持干细胞样表型和舒尼替尼耐药的重要机制，使PAK 1介导的NF-κB/IL-6激活作为对抗舒尼替尼耐药的新的药物治疗靶点具有相当大的吸引力。
The p21-activated kinase 1 (PAK1), a serine/threonine kinase that orchestrates cytoskeletal remodeling and cell motility, has been shown to function as downstream node for various oncogenic signaling pathways to promote cell proliferation, regulate apoptosis and accelerate mitotic abnormalities, resulting in tumor formation and invasiveness. Although alterations in PAK1 expression and activity have been detected in various human malignancies, its potential biological and clinical significance in renal cell carcinoma (RCC) remains obscure. In this study, we found increased PAK1 and phosphorylated PAK1 levels in tumor tissues according to TNM stage progression. Elevated phosphorylated PAK1 levels associated with progressive features and indicated unfavorable overall survival (OS) as an independent adverse prognosticator for patients with RCC. Moreover, PAK1 kinase activation with constitutive active PAK1 mutant T423E promoted growth, colony formation, migration, invasion and stem-like phenotype of RCC cells, and vice versa, in PAK1 inhibition by PAK1 kinase inactivation with specific PAK1 shRNA, dead kinase PAK1 mutant K299R or allosteric inhibitor IPA3. Stem-like phenotype due to sunitinib administration via increased PAK1 kinase activation could be ameliorated by PAK1 shRNA, PAK1 mutant K299R and IPA3. Furthermore, nuclear factor-κB (NF-κB)/interleukin-6 (IL-6) activation was found to be responsible for PAK1-mediated stem-like phenotype following sunitinib treatment. Both IL-6 neutralizing antibody and IPA3 administration enhanced tumor growth inhibition effect of sunitinib treatment on RCC cells in vitro and in vivo. Our results unraveled that oncogenic activation of PAK1 defines an important mechanism for maintaining stem-like phenotype and sunitinib resistance through NF-κB/IL-6 activation in RCC, lending PAK1-mediated NF-κB/IL-6 activation considerable appeal as novel pharmacological therapeutic targets against sunitinib resistance.