Search

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., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nur Akmarina B. M. Said reports financial support was provided by Malaysia Ministry of Higher Education. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Although epithelial-mesenchymal transition (EMT) and p53 have been established to play a pivotal role in the aggressiveness of muscle-invasive bladder cancer (MIBC), its pathological correlation to cisplatin treatment in the Malaysian patient cohort is lacking. This study aimed to evaluate the association of EMT markers, e-cadherin, vimentin and actin, as well as tumour suppressor gene, p53, in cisplatin-receiving MIBC patients., Materials and Methods: Formalin-fixed paraffinembedded (FFPE) blocks of muscle-invasive bladder cancer patients receiving cisplatin-based chemotherapy between January 2010 to December 2020 were traced. Immunohistochemistry staining was performed on traced blocks using antibodies to e-cadherin, vimentin and actin, and p53., Results: p53 and e-cadherin were stained positive in most cases (p=0.515 and 0.242 respectively), although e-cadherin showed stronger positive expression in pre-cisplatin receiving MIBC cases. All the cases stained negative for actin and vimentin except for faint staining observed in one pre-cisplatin case., Conclusion: Although this study does not show a significant correlation between EMT markers and p53 with cisplatin-responsiveness in MIBC patients, the results serve as preliminary findings on the heterogeneous outcomes of molecular staining in the Malaysian MIBC patient cohort.

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)