Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur, Malaysia.
School of Pharmacy, Monash University, Selangor, Malaysia.
Int J Biochem Cell Biol. 2024 Nov;176:106652. doi: 10.1016/j.biocel.2024.106652. Epub 2024 Sep 11.
Chemotherapy against muscle-invasive bladder cancer is increasingly challenged by the prevalence of chemoresistance. The cholesterol biosynthesis pathway has garnered attention in studies of chemoresistance, but conflicting clinical and molecular findings necessitate a clearer understanding of its underlying mechanisms. Recently, we identified farnesyl-diphosphate farnesyltransferase 1 (FDFT1)-the first specific gene in this pathway-as a tumor suppressor and chemoresistance modulator. Raman spectroscopy revealed higher levels of FDFT1-related metabolites in chemotherapy-sensitive bladder cancer tissue compared to resistant tissue; however, this observation lacks mechanistic insight. FDFT1 expression was reduced in our cisplatin-resistant bladder cancer cells (T24R) compared to parental cisplatin-sensitive cells (T24). Using functional knockdown and ectopic overexpression in T24/T24R cells, we mechanistically demonstrate the pathway through which FDFT1 mediates cisplatin sensitivity in bladder cancer cells. Bioinformatics analysis and rescue experiments showed that microRNA-146b-5p directly targets and downregulates FDFT1, reducing the cisplatin sensitivity of T24 cells, which can be restored by forced FDFT1 expression. Further investigation into the downstream cholesterol pathway revealed that FDFT1 suppression redirects its substrate toward the non-sterol branch of the pathway, as evidenced by the upregulation of non-sterol branch-associated genes and a reduced total cholesterol level in the sterol branch. Since the non-sterol pathway leads to the prenylation of isoprenoids and activation of Ras and Rho family proteins involved in cancer progression and chemoresistance, our findings suggest that redirection of the cholesterol biosynthesis pathway is a key mechanism underlying FDFT1-mediated cisplatin resistance in bladder cancer. The miR-146b-5p/FDFT1 axis represents a promising target for overcoming chemoresistance in bladder cancer.
针对肌肉浸润性膀胱癌的化疗越来越受到化疗耐药性流行的挑战。胆固醇生物合成途径在化疗耐药性研究中受到关注，但相互矛盾的临床和分子发现需要更清楚地了解其潜在机制。最近，我们确定了法呢基二磷酸法呢基转移酶 1（FDFT1）-该途径中的第一个特定基因-作为肿瘤抑制因子和化疗耐药调节剂。拉曼光谱显示，与耐药组织相比，化疗敏感膀胱癌组织中与 FDFT1 相关的代谢物水平更高；然而，这种观察缺乏机制上的洞察力。与亲本顺铂敏感细胞（T24）相比，我们的顺铂耐药膀胱癌细胞（T24R）中 FDFT1 的表达降低。在 T24/T24R 细胞中，通过功能敲低和异位过表达，我们从机制上证明了 FDFT1 介导膀胱癌细胞顺铂敏感性的途径。生物信息学分析和挽救实验表明，microRNA-146b-5p 直接靶向并下调 FDFT1，降低 T24 细胞的顺铂敏感性，这可以通过强制 FDFT1 表达来恢复。对下游胆固醇途径的进一步研究表明，FDFT1 抑制将其底物重新定向到非甾体分支途径，这表现在非甾体分支相关基因的上调和甾体分支中总胆固醇水平的降低。由于非甾体途径导致异戊烯基的 prenylation 和 Ras 和 Rho 家族蛋白的激活，这些蛋白参与癌症进展和化疗耐药性，我们的发现表明胆固醇生物合成途径的重定向是 FDFT1 介导膀胱癌顺铂耐药的关键机制。miR-146b-5p/FDFT1 轴代表克服膀胱癌化疗耐药性的有前途的靶点。
