Huang Zhilong, Wang Tingting, Xia Wenjun, Li Qing, Chen Xinlei, Liu Xiaoli, Wei Peng, Xu Wenping, Lv Meirong
Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.
Department of Anesthesia, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.
Exp Ther Med. 2020 Aug;20(2):1431-1440. doi: 10.3892/etm.2020.8856. Epub 2020 Jun 10.
A number of previous studies have demonstrated that inhibiting autophagy can increase the cellular cytotoxicity of chemotherapeutic agents in urothelial cancer cells. However, the mechanistic roles of autophagy in gemcitabine (GEM) resistant bladder cancer cells have not been thoroughly investigated. In the present study, immunohistochemistry staining of autophagy marker LC3 was performed in bladder cancer and healthy control tissues and demonstrated an essential role of autophagy in cancer development. A GEM-resistant cell line was established to assess the effects of autophagy on the acquisition of GEM resistance. Western blotting of autophagy markers in GEM-resistant bladder cancer cells suggested that GEM resistance was caused, at least partially, by GEM-induced autophagy. GEM resistance was demonstrated to be reversed by the inhibition of autophagy by 3-methyladenine. In addition, oblongifolin C (OC), a novel autophagic flux inhibitor purified from traditional Chinese medicine, was found to enhance the efficiency of GEM in GEM-resistant bladder cancer cells by inhibiting autophagic flux. In conclusion, data from the present study suggest that autophagy serves an important role in bladder cancer development and GEM resistance. OC treatment has the ability to reverse GEM-resistance in bladder cancer cells by suppressing autophagic flux, thereby providing a potential adjunctive therapeutic option for bladder cancer GEM treatment.
此前的多项研究表明，抑制自噬可增强化疗药物对尿路上皮癌细胞的细胞毒性。然而，自噬在吉西他滨（GEM）耐药膀胱癌细胞中的作用机制尚未得到充分研究。在本研究中，对膀胱癌组织和健康对照组织进行了自噬标志物LC3的免疫组织化学染色，结果表明自噬在癌症发展中起重要作用。建立了一种吉西他滨耐药细胞系，以评估自噬对吉西他滨耐药性获得的影响。对吉西他滨耐药膀胱癌细胞中的自噬标志物进行蛋白质印迹分析表明，吉西他滨耐药至少部分是由吉西他滨诱导的自噬引起的。结果表明，3-甲基腺嘌呤抑制自噬可逆转吉西他滨耐药性。此外，从中药中纯化得到的新型自噬流抑制剂长叶九里香素C（OC），被发现可通过抑制自噬流提高吉西他滨对吉西他滨耐药膀胱癌细胞的疗效。总之，本研究数据表明自噬在膀胱癌发展和吉西他滨耐药中起重要作用。OC治疗能够通过抑制自噬流逆转膀胱癌细胞的吉西他滨耐药性，从而为膀胱癌吉西他滨治疗提供一种潜在的辅助治疗选择。
