title: Isorhamnetin inhibits proliferation and invasion and induces apoptosis through the modulation of peroxisome proliferator-activated receptor γ activation pathway in gastric cancer.
abstract: Gastric cancer (GC) is a lethal malignancy and the second most common cause of cancer-related deaths. Although treatment options such as chemotherapy, radiotherapy, and surgery have led to a decline in the mortality rate due to GC, chemoresistance remains as one of the major causes for poor prognosis and high recurrence rate. In this study, we investigated the potential effects of isorhamnetin (IH), a 3'-O-methylated metabolite of quercetin on the peroxisome proliferator-activated receptor γ (PPAR-γ) signaling cascade using proteomics technology platform, GC cell lines, and xenograft mice model. We observed that IH exerted a strong antiproliferative effect and increased cytotoxicity in combination with chemotherapeutic drugs. IH also inhibited the migratory/invasive properties of GC cells, which could be reversed in the presence of PPAR-γ inhibitor. We found that IH increased PPAR-γ activity and modulated the expression of PPAR-γ regulated genes in GC cells. Also, the increase in PPAR-γ activity was reversed in the presence of PPAR-γ-specific inhibitor and a mutated PPAR-γ dominant negative plasmid, supporting our hypothesis that IH can act as a ligand of PPAR-γ. Using molecular docking analysis, we demonstrate that IH formed interactions with seven polar residues and six nonpolar residues within the ligand-binding pocket of PPAR-γ that are reported to be critical for its activity and could competitively bind to PPAR-γ. IH significantly increased the expression of PPAR-γ in tumor tissues obtained from xenograft model of GC. Overall, our findings clearly indicate that antitumor effects of IH may be mediated through modulation of the PPAR-γ activation pathway in GC.
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Lalitha
authors.initials: L
authors.lastname: Ramachandran
authors.forename: Kanjoormana Aryan
authors.initials: KA
authors.lastname: Manu
authors.forename: Muthu K
authors.initials: MK
authors.lastname: Shanmugam
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Kodappully Sivaraman
authors.initials: KS
authors.lastname: Siveen
authors.forename: Shireen
authors.initials: S
authors.lastname: Vali
authors.forename: Shweta
authors.initials: S
authors.lastname: Kapoor
authors.forename: Taher
authors.initials: T
authors.lastname: Abbasi
authors.forename: Rohit
authors.initials: R
authors.lastname: Surana
authors.forename: Duane T
authors.initials: DT
authors.lastname: Smoot
authors.forename: Hassan
authors.initials: H
authors.lastname: Ashktorab
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.forename: Kwang Seok
authors.initials: KS
authors.lastname: Ahn
authors.forename: Chun Wei
authors.initials: CW
authors.lastname: Yap
authors.forename: Alan Prem
authors.initials: AP
authors.lastname: Kumar
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D040901:Proteomics; D011794:Quercetin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D047495:PPAR gamma; C047368:3-methylquercetin; D011794:Quercetin