Antitumor activity of phenanthroindolizidine alkaloids is associated with negative regulation of met endosomal signaling in renal cancer cells

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.