title: Antitumor activity of phenanthroindolizidine alkaloids is associated with negative regulation of Met endosomal signaling in renal cancer cells.
abstract: Met is a receptor tyrosine kinase for hepatocyte growth factor. Met mutations have been considered as a major cause of primary resistance to Met tyrosine kinase inhibitors (TKIs). Mutated Met enhances its endosomal signaling, which includes internalization, signaling within endosomes, recycling to membrane, and sorting for degradation. These sequential events lead to a plausible mechanism for resistance. (-)-Antofine, a phenanthroindolizidine alkaloid, has exhibited potent antitumor activity but the precise underlying mechanism has been poorly understood. We found that (-)-antofine effectively inhibited the proliferation of Met-mutated Caki-1 cells, which were resistant to well-known Met TKIs. (-)-Antofine negatively regulated Met endosomal signaling and consequently inhibited the nuclear translocation of STAT3 both in vitro and in vivo. These findings emphasize the potential of Met endosomal signaling as a novel target for Met TKI-resistant cancers and (-)-antofine as a novel lead compound associated with the suppression of Met endosomal signaling.
authors: College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea.
authors: Jayoung
authors: J
authors: Song
authors: College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea.
authors: Yongseok
authors: Y
authors: Kwon
authors: College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea.
authors: Sanghee
authors: S
authors: Kim
authors: College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea. Electronic address: sklee61@snu.ac.kr.
authors: Sang Kook
authors: SK
authors: Lee
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D007212:Indolizines / Q000737:chemistry / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D018613:Microscopy, Confocal; D010618:Phenanthrolines / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D050721:Proto-Oncogene Proteins c-cbl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013237:Stereoisomerism
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D007211:Indoles; D007212:Indolizines; D010618:Phenanthrolines; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C473343:antofine; C521640:phenanthroindolizidine; D050721:Proto-Oncogene Proteins c-cbl; D019859:Proto-Oncogene Proteins c-met