Hedgehog Suppresses Paclitaxel Sensitivity by Regulating Akt-Mediated Phosphorylation of Bax in EGFR Wild-Type Non-Small Cell Lung Cancer Cells.
Hedgehog Suppresses Paclitaxel Sensitivity by Regulating Akt-Mediated Phosphorylation of Bax in EGFR Wild-Type Non-Small Cell Lung Cancer Cells.
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DOI：
10.3389/fphar.2022.815308
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发表时间：
2022
影响因子：
5.6
通讯作者：
Su BC
中科院分区：
文献类型：
--
作者：
Tu YC;Yeh WC;Yu HH;Lee YC;Su BC
非小细胞肺癌（NSCLC）是世界上最常见和最致命的癌症之一。在非小细胞肺癌患者中，几乎一半具有野生型表皮生长因子受体（EGFR WT）。这些EGFR WT NSCLC患者的主要治疗选择是化疗，而EGFR突变的NSCLC患者有更多样化的治疗选择，包括EGFR酪氨酸激酶抑制剂。此外，EGFR WT NSCLC患者的化疗反应比EGFR突变NSCLC患者差。因此，迫切需要新的治疗策略来改善EGFR WT NSCLC患者的化疗反应。已知Hedgehog信号在NSCLC中高度活跃;然而，其在化疗耐药性中的潜在作用尚未完全了解。在本研究中，我们发现紫杉醇（PTX）处理诱导EGFR WT NSCLC细胞中的hedgehog信号传导，并且用GDC-0449（Vismodegib）抑制hedgehog信号传导增加对PTX刺激的细胞凋亡的敏感性。此外，GDC-0449增强PTX诱导的活性氧和线粒体功能障碍。相反，hedgehog激动剂Hh-Ag 1.5减弱PTX诱导的细胞凋亡。机制实验表明，刺猬诱导Akt的丝氨酸473磷酸化。然后Akt在Ser 184处磷酸化Bax，这可以将其活性从促凋亡转变为抗凋亡。总之，我们的研究结果表明，抑制hedgehog信号传导可能是一种有前途的治疗策略，以改善EGFR WT NSCLC的PTX反应。
Non-small cell lung cancer (NSCLC) is one of the most common and deadly cancers worldwide. Among NSCLC patients, almost half have wild-type epidermal growth factor receptor (EGFR WT). The primary therapeutic option for these EGFR WT NSCLC patients is chemotherapy, while NSCLC patients with EGFR mutations have more diverse therapeutic options, including EGFR tyrosine kinase inhibitors. Moreover, NSCLC patients with EGFR WT have worse chemotherapy response than EGFR mutant NSCLC patients. Thus, an urgent need exists for novel therapeutic strategies to improve chemotherapy response in EGFR WT NSCLC patients. Hedgehog signaling is known to be highly active in NSCLC; however, its potential role in chemoresistance is not fully understood. In the present study, we found that paclitaxel (PTX) treatment induces hedgehog signaling in EGFR WT NSCLC cells, and inhibition of hedgehog signaling with GDC-0449 (Vismodegib) increases sensitivity to PTX-stimulated apoptosis. Furthermore, GDC-0449 potentiates PTX-induced reactive oxygen species and mitochondrial dysfunction. In contrast, a hedgehog agonist, Hh-Ag1.5, attenuates PTX-induced apoptosis. Mechanistic experiments revealed that hedgehog induces phosphorylation of Akt at Ser473. Akt then phosphorylates Bax at Ser184, which can switch its activity from pro-apoptosis to anti-apoptosis. Taken together, our findings suggest that inhibition of hedgehog signaling might be a promising therapeutic strategy to improve PTX response in EGFR WT NSCLC.
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