Sun Shanshan, Wu Hao, Wu Xiaohong, You Zilong, Jiang Yang, Liang Xiaoshuan, Chen Zhuo, Zhang Ye, Wei Wei, Jiang Yongdong, Chen Yanbo, Song Yanni, Pang Da
Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China.
Sino-Russian Medical Research Center, Heilongjiang Academy of Medical Sciences, Harbin, China.
Front Oncol. 2021 Mar 4;11:535230. doi: 10.3389/fonc.2021.535230. eCollection 2021.
Triple negative breast cancer (TNBC) is known to have aggressive clinical course and a high risk of recurrence. Given the lack of effective targeted therapy options, paclitaxel-based chemotherapy is still the primary option for TNBC patients. However, patients who fail to achieve a complete response during neoadjuvant chemotherapy may be mainly due to sensitivity and resistance to chemotherapy. Thus, we concentrated the present research on the role of PGK1 in the sensitivity to paclitaxel treatment and the possible underlying mechanisms in TNBC. After exposure to paclitaxel, a cell viability analysis was made to investigate the influence of PGK1 silencing on cell death. The effect of PGK1 on apoptosis induced by paclitaxel treatment was examined by flow cytometry cell apoptosis assays. Western blotting was performed to examine the impact of PGK1 on paclitaxel-induced apoptosis. The correlation of PGK1 with apoptosis-associated protein X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) was analyzed in 39 specimens by immunohistochemistry analysis. We observed that silencing PGK1 sensitized triple-negative breast cancer (TNBC) cell lines to paclitaxel treatment as a result of increased drug-induced apoptosis. Furthermore, mechanistic investigations suggested that XAF1 was increased in PGK1-knockdown cells along with the expression of the apoptotic proteins including cleaved caspase-3 and Bax. Immunohistochemistry analysis showed that PGK1 was negatively related to XAF1. Moreover, we found that downregulation of XAF1 reduced paclitaxel-induced apoptosis in PGK1-silenced triple-negative cell lines. Our results identified PGK1 as a potential biomarker for the treatment of TNBC, and inhibition of PGK1 expression might represent a novel strategy to sensitize TNBC to paclitaxel treatment.
三阴性乳腺癌（TNBC）具有侵袭性的临床病程和较高的复发风险。鉴于缺乏有效的靶向治疗选择，基于紫杉醇的化疗仍是TNBC患者的主要治疗选择。然而，新辅助化疗期间未能达到完全缓解的患者可能主要是由于对化疗的敏感性和耐药性。因此，我们将本研究集中于PGK1在紫杉醇治疗敏感性中的作用以及TNBC中可能的潜在机制。在暴露于紫杉醇后，进行细胞活力分析以研究PGK1沉默对细胞死亡的影响。通过流式细胞术细胞凋亡检测来检查PGK1对紫杉醇治疗诱导的凋亡的作用。进行蛋白质免疫印迹法以检查PGK1对紫杉醇诱导的凋亡的影响。通过免疫组织化学分析在39个标本中分析PGK1与凋亡相关蛋白X连锁凋亡抑制蛋白（XIAP）相关因子1（XAF1）的相关性。我们观察到，沉默PGK1使三阴性乳腺癌（TNBC）细胞系对紫杉醇治疗敏感，这是由于药物诱导的凋亡增加所致。此外，机制研究表明，在PGK1敲低的细胞中，XAF1增加，同时包括裂解的半胱天冬酶-3和Bax在内的凋亡蛋白的表达也增加。免疫组织化学分析表明PGK1与XAF1呈负相关。此外，我们发现下调XAF1可降低PGK1沉默的三阴性细胞系中紫杉醇诱导的凋亡。我们的结果确定PGK1是治疗TNBC的潜在生物标志物，抑制PGK1表达可能代表一种使TNBC对紫杉醇治疗敏感的新策略。
