靶向瞬时受体电位香草酸亚型1通过抑制PI3K/AKT信号通路降低非小细胞肺癌的化疗耐药性和干性。
Targeting transient receptor potential canonical 1 reduces non‑small cell lung cancer chemoresistance and stemness via inhibition of PI3K/AKT signaling.
作者信息
Jin Jiahui, Yan Xinyu, Zhao Yaru, Zhang Haojie, Zhuang Kai, Wen Yating, He Jingjing, Gao Junzhen
机构信息
Department of Oncology, Affiliated Qingdao Central Hospital, Qingdao University, Qingdao, Shandong 266042, P.R. China.
Department of Respiratory and Critical Care Medicine, The Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region 010050, P.R. China.
出版信息
Oncol Lett. 2023 Apr 13;25(6):224. doi: 10.3892/ol.2023.13810. eCollection 2023 Jun.
TRPC1 enhances cell proliferation and migration in non-small cell lung cancer (NSCLC); however, its effect on NSCLC chemoresistance and stemness remains to be determined. The aim of the current study was to investigate the effect of TRPC1 on NSCLC chemoresistance and stemness and to determine the underlying mechanism of action. Cisplatin-resistant A549 (A549/CDDP) and H460 (H460/CDDP) cells were first established and were then transfected with negative control small interfering (si)RNA (si-NC) or TRPC1 siRNA (si-TRPC1). Cells were then treated with 740 Y-P, a PI3K/Akt agonist. Subsequently, the sensitivity of A549/CDDP and H460/CDDP cells to CDDP was evaluated. Furthermore, the expression levels of CD133 and CD44, and sphere formation ability were also determined. The results showed that the half-maximal inhibitory concentration (IC) of CDDP was significantly higher in A549/CDDP cells compared with A549 cells and in H460/CDDP cells compared with H460 cells. TRPC1 silencing decreased the IC value of CDDP compared with the si-NC group in A549/CDDP (11.78 vs. 21.58 µM; P<0.01) and H460/CDDP (23.76 vs. 43.11 µM; P<0.05) cells. Additionally, TRPC1 knockdown in both cell lines decreased the number of spheres formed compared with the si-NC group. Furthermore, compared with the si-NC group, A549/CDDP cells transfected with si-TRPC1 exhibited decreased levels of both CD133 (P<0.01) and CD44 (P<0.05). However, only CD133 (P<0.05) was downregulated in TRPC1-depleted H460/CDDP cells compared with the si-NC group. In addition, TRPC1 knockdown repressed PI3K/AKT signaling compared with the si-NC group in both A549/CDDP and H460/CDDP cells (all P<0.05). Finally, cell treatment with 740 Y-P reversed the effect of TRPC1 knockdown on PI3K/AKT signaling, chemoresistance, and cancer stemness in A549/CDDP and H460/CDDP cells (all P<0.05). In conclusion, the results of the current study suggested that targeting TRPC1 could attenuate cancer stemness and chemoresistance via suppression of PI3K/AKT signaling in NSCLC.
瞬时受体电位通道蛋白1（TRPC1）可增强非小细胞肺癌（NSCLC）的细胞增殖和迁移；然而，其对NSCLC化疗耐药性和干性的影响仍有待确定。本研究的目的是探讨TRPC1对NSCLC化疗耐药性和干性的影响，并确定其潜在的作用机制。首先建立顺铂耐药的A549（A549/CDDP）和H460（H460/CDDP）细胞系，然后用阴性对照小干扰（si）RNA（si-NC）或TRPC1 siRNA（si-TRPC1）进行转染。随后用PI3K/Akt激动剂740 Y-P处理细胞。接着评估A549/CDDP和H460/CDDP细胞对顺铂的敏感性。此外，还测定了CD133和CD44的表达水平以及成球能力。结果显示，与A549细胞相比，A549/CDDP细胞中顺铂的半数最大抑制浓度（IC）显著更高；与H460细胞相比，H460/CDDP细胞中顺铂的IC也显著更高。与si-NC组相比，在A549/CDDP（11.78对21.58 μM；P<0.01）和H460/CDDP（23.76对43.11 μM；P<0.05）细胞中，TRPC1基因沉默降低了顺铂的IC值。此外，与si-NC组相比，两种细胞系中TRPC1基因敲低均减少了形成的球体数量。而且，与si-NC组相比，用si-TRPC1转染的A549/CDDP细胞中CD133（P<0.01）和CD44（P<0.05）的水平均降低。然而，与si-NC组相比，在TRPC1基因敲低的H460/CDDP细胞中只有CD133（P<0.05）表达下调。另外，与si-NC组相比，在A549/CDDP和H460/CDDP细胞中TRPC1基因敲低均抑制了PI3K/AKT信号通路（所有P<0.05）。最后，用740 Y-P处理细胞逆转了TRPC1基因敲低对A549/CDDP和H460/CDDP细胞中PI3K/AKT信号通路、化疗耐药性和癌症干性的影响（所有P<0.05）。总之，本研究结果表明，靶向TRPC1可通过抑制NSCLC中的PI3K/AKT信号通路来减弱癌症干性和化疗耐药性。
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