RESUMEN
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.
RESUMEN
As is the case for most solid tumours, chemotherapy remains the backbone in the management of metastatic disease. However, the occurrence of chemotherapy resistance is a cause to worry, especially in bladder cancer. Extensive evidence indicates molecular changes in bladder cancer cells to be the underlying cause of chemotherapy resistance, including the reduced expression of farnesyl-diphosphate farnesyltransferase 1 (FDFT1) - a gene involved in cholesterol biosynthesis. This can likely be a hallmark in examining the resistance and sensitivity of chemotherapy drugs. This work performs spectroscopic analysis and metabolite characterization on resistant, sensitive, stable-disease and healthy bladder tissues. Raman spectroscopy has detected peaks at around 1003 cm-1 (squalene), 1178 cm-1 (cholesterol), 1258 cm-1 (cholesteryl ester), 1343 cm-1 (collagen), 1525 cm-1 (carotenoid), 1575 cm-1 (DNA bases) and 1608 cm-1 (cytosine). The peak parameters were examined, and statistical analysis was performed on the peak features, attaining significant differences between the sample groups. Small-angle x-ray scattering (SAXS) measurements observed the triglyceride peak together with 6th, 7th and 8th - order collagen peaks; peak parameters were also determined. Neutron activation analysis (NAA) detected seven trace elements. Carbon (Ca), magnesium (Mg), chlorine (Cl) and sodium (Na) have been found to have the greatest concentration in the sample groups, suggestive of a role as a biomarker for cisplatin resistance studies. Results from the present research are suggested to provide an important insight into understanding the development of drug resistance in bladder cancer, opening up the possibility of novel avenues for treatment through personalised interventions.
Asunto(s)
Cisplatino , Resistencia a Antineoplásicos , Espectrometría Raman , Neoplasias de la Vejiga Urinaria , Humanos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Cisplatino/farmacología , Cisplatino/uso terapéutico , Farnesiltransferasa/metabolismo , Espectrometría Raman/métodos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Difracción de Rayos X , Farnesil Difosfato Farnesil Transferasa/metabolismoRESUMEN
Successful treatment for muscle-invasive bladder cancer is challenged by the ability of cancer cells to resist chemotherapy. While enormous progress has been made toward understanding the divergent molecular mechanisms underlying chemoresistance, the heterogenous interplay between the bladder tumour and its microenvironment presents significant challenges in comprehending the occurrence of chemoresistance. The last decade has seen exponential interest in the exploration of microRNA (miRNA) as a tool in the management of chemoresistance. In this review, we highlight the miRNAs involved in the tumour microenvironment crosstalk that contributes to the chemoresistance in bladder cancer. Decrypting the role of miRNAs in the interplay beholds scope for future clinical translational application in managing the long-standing concerns of chemoresistance in muscle-invasive bladder cancer.