Abstract
Chemotherapy, a major cancer treatment approach, suffers seriously from multidrug resistance (MDR), generally caused by innate DNA repair proteins that reverse the DNA modification by anti-cancer therapeutics or trans-membrane efflux proteins that pump anti-cancer therapeutics out of the cytosol. This project focused on finding microRNAs that can regulate MDR proteins by managing corresponding mRNA levels through post-transcriptional regulation based on nucleotide sequence matching. Screening was done with bioinformatics databases for unpublished/unexplored microRNAs with high nucleotide sequence correspondence to two representative MDR proteins, MGMT (a DNA repair protein) and ABCB1 (an efflux protein), revealing microRNA-4539 and microRNA-4261 respectively. To investigate the enhancement of chemotherapeutics in cancer cells, high MGMT expressing glioblastoma (T98G) and a high ABCB1 expressing triple-negative breast cancer cell line (MDA-MB-231-luc) were treated with varying concentrations of chemotherapeutics and corresponding miRNAs. Newly identified MDR-related miRNAs (MDRmiRs) enhanced the response to anti-cancer therapeutics and resulted in effective cell death. In this study, we demonstrated that therapeutic miRNAs could be identified based on the nucleotide sequence matching of miRNAs to targeted mRNA and the same approach could be employed for the screening of therapeutic candidates to regulate specific target proteins in diverse diseases.
Highlights
Cancer is the second leading cause of death worldwide, with approximately 42% of men and 38% of women being diagnosed with cancer in their lifetimes[1]
A list of MDR-related miRNAs (MDRmiRs) was identified as tentative therapeutics and two microRNAs were selected with highest sequence matching to target mRNAs
We investigated the therapeutic effects of MDRmiRs for the enhancement of chemotherapeutics using a glioma cell line (T98G) with high methylguanine methyltransferase (MGMT) expression and a triple-negative breast cancer cell line (MDA-MB-231-luc) with high ATP Binding Cassette Subfamily B Member 1 (ABCB1) expression
Summary
Cancer is the second leading cause of death worldwide, with approximately 42% of men and 38% of women being diagnosed with cancer in their lifetimes[1]. Out of many MDR mechanisms, it is relatively well characterized that trans-membrane efflux proteins can pump the drug molecules out of the cancer cells to prevent the interaction with their targets, inducing multi-drug resistance, which is challenging to overcome in clinical anti-cancer treatment. Representatives of these efflux proteins include ATP-binding cassette subfamily B member 1 (ABCB1/MDR1), multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein (BCRP/ABCG2)[4]. We investigated the therapeutic effects of MDRmiRs for the enhancement of chemotherapeutics using a glioma cell line (T98G) with high MGMT expression and a triple-negative breast cancer cell line (MDA-MB-231-luc) with high ABCB1 expression
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