Expression and regulation of efflux transporters in chemoresistant breast, colon and ovarian cancer cells in Bangladeshi patients

Abstract

Chemotherapy is a cornerstone in cancer treatment, but multidrug resistance (MDR) poses a substantial challenge. Hyperactivity of efflux pumps is one of the vital reasons to confer MDR. P-GP, MRP1 and ABCG2- these key ABC efflux pumps collectively transport a spectrum of chemotherapeutic drugs out of cells. HIF1A, a master regulator, is also associated with cancer biology, influencing cellular invasion, angiogenesis and metabolism. HuR regulates the expression of various carcinogenic molecules by mRNA trafficking, stabilization and enhancement of protein translation as well. Thereby this study addresses a crucial research gap in Bangladeshi population by inspecting the expression patterns of P-GP, MRP1 and ABCG2 in chemoresistant breast, colorectal and ovarian tissues. This study also aimed to delve into the mechanisms of drug resistance, focusing on HIF1A and HuR driven overexpression of ABC transporters, thus leading to chemoresistance. In this prospective study, 57 (chemoresistant) and 57 (paired control) tissue samples from Bangladeshi cancer patients were processed for immunofluorescence staining. The data showed the consistent co-expression of P-GP, MRP1 and ABCG2 across all cases, suggesting a potential synergistic function of transporter proteins in chemoresistance. The observations from this study also revealed that HIF1A and HuR overexpress in chemoresistant tissues, suggesting their pivotal role in chemoresistance mechanisms across malignancies and potential as therapeutic targets in Bangladeshi population. This study also suggests a direct regulation of P-GP, MRP1 and ABCG2 transcription by HIF1A that binds to the 'CGTG' sequence in the promoter regions. Besides, HuR might facilitate posttranscriptional mRNA stabilization by interacting with AU-rich elements (AREs) in the 3'UTR regions of the ABC transporters. Inhibition of these interactions of HIF1A and HuR appears as a promising approach to reverse chemoresistance. Thus, this study offers constructive insights for designing more efficient treatment strategies.