A novel lncRNA-responsive and xenobiotic receptor-mediated regulation of drug metabolism and disposition Abstract Drug metabolism and disposition are essential xenobiotic responses. The long non-coding RNAs (lncRNAs) are non-coding RNAs larger than 200 nucleotides (nt) in length and do not have protein-coding potentials. Although many of the biological functions of lncRNAs have been recognized, it is unclear whether and how lncRNAs can regulate the expression of drug-metabolizing enzymes and transporters and if so, whether the regulations are implicated in cancer chemo-resistance. Through integrative analysis of cancer non-coding genomic and high-through drug screening data of 505 cancer cell lines, our preliminary study have discovered and functionally characterized a group of ADME(drug absorption, distribution, metabolism, and excretion) chemo-resistance lncRNAs, including LINC00992, whose up-regulation is associated with resistance to more than 100 chemotherapy compounds and may regulate drug-metabolizing enzymes and transporters through interacting with xenobiotic nuclear receptor. We hypothesize that dysregulation of ADME chemo-resistance lncRNAs is an important contributor for the development of cancer chemo-resistance. Mechanistically, ADME chemo-resistance lncRNAs affect chemo-resistance through their regulation of drug-metabolizing enzymes and transporters that are responsible for the metabolism and disposition of chemotherapy drugs. We propose three specific aims to test our hypotheses:
In Aim 1, we will perform bioinformatic analysis and molecularly clone of lncRNAs associated with cancer chemo-resistance and clinical prognosis.
In Aim 2 : we will functional characterize of ADME chemo-resistance lncRNAs, including LINC00992, using in vivo and in vitro cancer chemotherapy models.
In Aim 3 : we will determine the mechanism by which ADME chemo-resistance lncRNAs, including LINC00992, regulate the expression of drug-metabolizing enzymes and transporters. Chemotherapy remains a mainstay in the clinical management of cancer patients, but chemo-resistance is a major challenge to overcome. Understanding the novel lncRNA responsive and xenobiotic nuclear receptor- mediated chemo-resistance will help provide novel strategies to enhance therapeutic efficacy and avoid the development of chemo-resistance.
The goal of this study is to reveal a novel lncRNA-responsive and xenobiotic receptor-mediated regulation of drug metabolism and disposition. Specifically, we propose to test the hypothesis that a group of novel lncRNAs, identified by our computational analysis and experimental validation, can affect chemo-resistance through their regulation of drug-metabolizing enzymes and transporters that are responsible for the metabolism and disposition of chemotherapy drugs. Understanding the novel lncRNA responsive and xenobiotic nuclear receptor-mediated chemo-resistance will help provide novel strategies to enhance therapeutic efficacy and avoid the development of chemo-resistance.
