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Golovine K , Makhov P , Naito S , Raiyani H , Tomaszewski J , Mehrazin R , Tulin A , Kutikov A , Uzzo RG , Kolenko VM
Piperlongumine and its analogs down-regulate expression of c-Met in renal cell carcinoma
Cancer Biol Ther. 2015 May;16(5) :743-749
PMID: 25801713    PMCID: PMC4623021    URL: http://www.ncbi.nlm.nih.gov/pubmed/25801713
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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-kappaB 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.
Golovine, Konstantin Makhov, Peter Naito, Sei Raiyani, Henish Tomaszewski, Jeffrey Mehrazin, Reza Tulin, Alexei Kutikov, Alexander Uzzo, Robert G. Kolenko, Vladimir M.