Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China.
Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, No. 1838, Guangzhou Avenue North, 510515, Guangzhou, China.
Cell Death Dis. 2022 Jul 28;13(7):658. doi: 10.1038/s41419-022-05118-8.
Chemoresistance remains the primary challenge of clinical treatment of gastric cancer (GC), making the biomarkers of chemoresistance crucial for treatment decision. Our previous study has reported that p21-actived kinase 6 (PAK6) is a prognostic factor for selecting which patients with GC are resistant to 5-fluorouracil/oxaliplatin chemotherapy. However, the mechanistic role of PAK6 in chemosensitivity remains unknown. The present study identified PAK6 as an important modulator of the DNA damage response (DDR) and chemosensitivity in GC. Analysis of specimens from patients revealed significant associations between the expression of PAK6 and poorer stages, deeper invasion, more lymph node metastases, higher recurrence rates, and resistance to oxaliplatin. Cells exhibited chemosensitivity to oxaliplatin after knockdown of PAK6, but showed more resistant to oxaliplatin when overexpressing PAK6. Functionally, PAK6 mediates cancer chemoresistance by enhancing homologous recombination (HR) to facilitate the DNA double-strand break repair. Mechanistically, PAK6 moves into nucleus to promote the activation of ATR, thereby further activating downstream repair protein CHK1 and recruiting RAD51 from cytoplasm to the DNA damaged site to repair the broken DNA in GC. Activation of ATR is the necessary step for PAK6 mediated HR repair to protect GC cells from oxaliplatin-induced apoptosis, and ATR inhibitor (AZD6738) could block the PAK6-mediated HR repair, thereby reversing the resistance to oxaliplatin and even promoting the sensitivity to oxaliplatin regardless of high expression of PAK6. In conclusion, these findings indicate a novel regulatory mechanism of PAK6 in modulating the DDR and chemoresistance in GC and provide a reversal suggestion in clinical decision.
化学耐药性仍然是胃癌（GC）临床治疗的主要挑战，因此化学耐药性的生物标志物对于治疗决策至关重要。我们之前的研究报告称，p21 激活激酶 6（PAK6）是预测 GC 患者对 5-氟尿嘧啶/奥沙利铂化疗耐药的预后因素。然而，PAK6 在化学敏感性中的机制作用尚不清楚。本研究确定 PAK6 是 GC 中 DNA 损伤反应（DDR）和化学敏感性的重要调节剂。对患者标本的分析表明，PAK6 的表达与较差的分期、更深的侵袭、更多的淋巴结转移、更高的复发率以及对奥沙利铂的耐药性之间存在显著关联。敲低 PAK6 后，细胞对奥沙利铂表现出化学敏感性，但过表达 PAK6 时，对奥沙利铂的耐药性增强。功能上，PAK6 通过增强同源重组（HR）来介导癌症化学耐药性，从而促进 DNA 双链断裂修复。在机制上，PAK6 进入细胞核以促进 ATR 的激活，从而进一步激活下游修复蛋白 CHK1，并从细胞质招募 RAD51 到 DNA 损伤部位，以修复 GC 中的断裂 DNA。ATR 的激活是 PAK6 介导的 HR 修复保护 GC 细胞免受奥沙利铂诱导的细胞凋亡所必需的步骤，ATR 抑制剂（AZD6738）可阻断 PAK6 介导的 HR 修复，从而逆转奥沙利铂耐药性，甚至在 PAK6 高表达的情况下促进对奥沙利铂的敏感性。总之，这些发现表明 PAK6 在调节 GC 中 DDR 和化学耐药性方面存在新的调控机制，并为临床决策提供了逆转建议。
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