title: Luteolin potentiates the sensitivity of colorectal cancer cell lines to oxaliplatin through the PPARγ/OCTN2 pathway.
abstract: Oxaliplatin is a chemotherapeutic agent used in the treatment of colorectal cancers. However, the mechanism controlling the cellular uptake and efflux of oxaliplatin is not completely understood. Organic cation/carnitine transporter 2 (OCTN2) is a member of the solute carrier superfamily and is a determinant of oxaliplatin uptake. OCTN2 is regulated by peroxisome proliferator-activated receptor γ (PPARγ) binding to the PPAR-response element within the first intron. Luteolin is a naturally occurring flavonoid and an agonist of PPARγ. Thus, we hypothesize that luteolin-mediated OCTN2 expression and activity potentiate the sensitivity of cancer cells to oxaliplatin. In this study, luteolin increased mRNA and protein expression of OCTN2 in a time-dependent and dose-dependent manner in colorectal cancer SW480 cells. This induction was attenuated by PPARγ antagonist GW9662 as well as by PPARγ knockdown, suggesting that the induction by luteolin is dependent on PPARγ. In uptake studies, luteolin increased the binding affinity of OCTN2 toward oxaliplatin and enhanced intracellular concentration of oxaliplatin. This finding is likely because of the increase of PDZ domain containing 1 (PDZK1) and PDZ domain containing 3 (PDZK2), which are known to facilitate the expression of OCTN2 on the cell surface and/or enhance transporter activity. Moreover, cell viability and cell apoptosis assays showed that luteolin increased oxaliplatin uptake and intracellular accumulation through OCTN2. Thus, our study showed that luteolin increased the sensitivity of colorectal cancer SW480 cells to oxaliplatin, likely through the PPARγ/OCTN2 pathway.
authors: aDepartment of Pharmacy bInstitute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics cDepartment of Surgery, Xiangya Hospital, Central South University, Changsha, China.
authors: Qiang
authors: Q
authors: Qu
authors: Jian
authors: J
authors: Qu
authors: Yong
authors: Y
authors: Guo
authors: Bo-Ting
authors: BT
authors: Zhou
authors: Hong-Hao
authors: HH
authors: Zhou
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000473:pathology*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D047311:Luteolin / Q000494:pharmacology*; D008565:Membrane Proteins; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D015398:Signal Transduction; D000074058:Solute Carrier Family 22 Member 5
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D048868:Adaptor Proteins, Signal Transducing; D000813:Anilides; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D027701:Organic Cation Transport Proteins; D009944:Organoplatinum Compounds; C423943:PDZD2 protein, human; C484659:PDZK1 protein, human; D047495:PPAR gamma; D047490:Retinoid X Receptor alpha; C492020:SLC22A5 protein, human; D000074058:Solute Carrier Family 22 Member 5; D000077150:Oxaliplatin; D047311:Luteolin