Zhang Zhengle, Chen Longjiang, Zhao Chuanbing, Gong Qiong, Tang Zhigang, Li Hanjun, Tao Jing
Department of Pancreatic Surgery, Renmin Hospital, Wuhan University, 238 Jiefang Road, Wuhan, 430060, Hubei Province, China.
Cell Biol Toxicol. 2023 Aug;39(4):1549-1560. doi: 10.1007/s10565-022-09746-w. Epub 2022 Aug 1.
Gemcitabine resistance is a frequently occurring and intractable obstacle in pancreatic cancer treatment. However, the underlying mechanisms require further investigation. Adaptive regulation of oxidative stress and aberrant activation of the NF-κB signaling pathway are associated with resistance to chemotherapy. Here, we found that gemcitabine upregulated the expression of CASC9 in a dose-dependent manner, partially via induction of reactive oxygen species, whereas inhibition of CASC9 expression enhanced gemcitabine-induced oxidative stress and apoptosis in pancreatic cancer cells. Furthermore, suppression of CASC9 level inhibited the expression of NRF2 and the downstream genes NQO1 and HO-1, and vice versa, indicating that CASC9 forms a positive feedback loop with NRF2 signaling and modulates the level of oxidative stress. Silencing CASC9 attenuated NF-κB pathway activation in pancreatic cancer cells and synergistically enhanced the cytotoxic effect of gemcitabine chemotherapy in vivo. In conclusion, our findings suggest that CASC9 plays a key role in driving resistance to gemcitabine through a reciprocal loop with the NRF2-antioxidant signaling pathway and by activating NF-κB signaling. Our study reveals potential targets that can effectively reverse resistance to gemcitabine chemotherapy.
吉西他滨耐药是胰腺癌治疗中经常出现且难以解决的障碍。然而，其潜在机制仍需进一步研究。氧化应激的适应性调节和NF-κB信号通路的异常激活与化疗耐药相关。在此，我们发现吉西他滨以剂量依赖的方式上调CASC9的表达，部分是通过诱导活性氧，而抑制CASC9表达可增强吉西他滨诱导的胰腺癌细胞氧化应激和凋亡。此外，抑制CASC9水平可抑制NRF2及其下游基因NQO1和HO-1的表达，反之亦然，表明CASC9与NRF2信号形成正反馈环并调节氧化应激水平。沉默CASC9可减弱胰腺癌细胞中NF-κB通路的激活，并在体内协同增强吉西他滨化疗的细胞毒性作用。总之，我们的研究结果表明，CASC9通过与NRF2-抗氧化信号通路形成相互作用环并激活NF-κB信号，在驱动吉西他滨耐药中起关键作用。我们的研究揭示了可有效逆转吉西他滨化疗耐药的潜在靶点。
