title: Anticancer effect of luteolin is mediated by downregulation of TAM receptor tyrosine kinases, but not interleukin-8, in non-small cell lung cancer cells.
abstract: TAM receptor tyrosine kinases (RTKs), Tyro3, Axl and MerTK, transduce diverse signals responsible for cell survival, growth, proliferation and anti-apoptosis. In the present study, we demonstrated the effect of luteolin, a flavonoid with antioxidant, anti-inflammatory and anticancer activities, on the expression and activation of TAM RTKs and the association with its cytotoxicity in non-small cell lung cancer (NSCLC) cells. We observed the cytotoxic effect of luteolin in parental A549 and H460 cells as well as in cisplatin-resistant A549/CisR and H460/CisR cells. Exposure of these cells to luteolin also resulted in a dose‑dependent decrease in clonogenic ability. Next, luteolin was found to decrease the protein levels of all three TAM RTKs in the A549 and A549/CisR cells in a dose‑dependent manner. In a similar manner, in H460 and H460/CisR cells, the protein levels of Axl and Tyro3 were decreased following luteolin treatment. In addition, Axl promoter activity was decreased by luteolin, indicating that luteolin suppresses Axl expression at the transcriptional level. We next found that luteolin abrogated Axl phosphorylation in response to growth arrest-specific 6 (Gas6), its ligand, implying the inhibitory effect of luteolin on Gas6-induced Axl activation. Ectopic expression of Axl was observed to attenuate the antiproliferative effect of luteolin, while knockdown of the Axl protein level using a gold nanoparticle-assisted gene delivery system increased its cytotoxicity. In contrast to the inhibitory effect of luteolin on the expression of TAM RTKs, interleukin-8 (IL-8) production was not decreased by luteolin in H460 and H460/CisR cells, while IL-8 production/cell was increased. Collectively, our data suggest that TAM RTKs, but not IL-8, are promising therapeutic targets of luteolin to abrogate cell proliferation and to overcome chemoresistance in NSCLC cells.
authors.affiliation: Department of Pharmacology, College of Medicine, Catholic University of Daegu, Daegu 47472, Republic of Korea.
authors.forename: Youn Ju
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
authors.forename: Taeho
authors.initials: T
authors.lastname: Lim
authors.affiliation: Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
authors.forename: Min Su
authors.initials: MS
authors.lastname: Han
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 40161, Republic of Korea.
authors.forename: Sun-Hwa
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Yeungnam University, Daegu 42415, Republic of Korea.
authors.forename: Suk-Hwan
authors.initials: SH
authors.lastname: Baek
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Yeungnam University, Daegu 42415, Republic of Korea.
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Nan
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Yeungnam University, Daegu 42415, Republic of Korea.
authors.forename: Chuhee
authors.initials: C
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047311:Luteolin / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D000970:Antineoplastic Agents; C508606:CXCL8 protein, human; D016209:Interleukin-8; D011518:Proto-Oncogene Proteins; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; C084944:TYRO3 protein, human; D000076202:c-Mer Tyrosine Kinase; D047311:Luteolin; D002945:Cisplatin; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human