The c-Met protein, a transmembrane receptor tyrosine kinase, is the product of a proto-oncogene. Its only known ligand, hepatocyte growth factor (HGF), regulates cell growth, motility, migration, invasion, proliferation, and angiogenesis. The aberrant expression of c-Met is often associated with poor prognosis in multiple cancers, including renal cell carcinoma (RCC). Silencing or inactivation of c-Met leads to decreased viability of cancer cells, thereby making ablation of c-Met signaling an attractive concept for developing novel strategies for the treatment of renal tumors. Naturally-occurring products or substances are the most consistent source of drug development. As such, we investigated the functional impact of piperlongumine (PL), a naturally occurring alkaloid present in the Long pepper (Piper longum) on c-Met expression in RCC cells and demonstrated that PL and its analogs rapidly reduce c-Met protein and RNA levels in RCC cells via ROS-dependent mechanism. PL-mediated c-Met depletion coincided with the inhibition of downstream c-Met signaling; namely Erk/MAPK, STAT3, NF-κB and Akt/mTOR. As such, PL and PL analogs hold promise as potential therapeutic agents for the treatment of metastatic RCC and the prevention of postoperative RCC recurrence.
Keywords: Erk, Extracellular signal-regulated kinase; FAK, Focal adhesion kinase; HGF, Hepatocyte growth factor; MAPK, Mitogen-activated protein kinase; NF-kB, Nuclear factor kappaB; PL, Piperlongumine; PL-Di, PL-Dimer; PL-FPh, PL-fluorophenyl; RCC, Renal cell carcinoma; RECIST, Response evaluation criteria in solid tumors; RNA, Ribonucleic acid; ROS; ROS, Reactive oxygen species; STAT, Signal transducer and activator of transcription; TKIs, Tyrosine kinase inhibitors; VEGFR, Vascular endothelial growth factor receptor; c-Met; cancer; mTOR, Mammalian target of rapamycin; piperlongumine; renal.