Piperlongumine and its analogs down-regulate expression of c-Met in renal cell carcinoma

Konstantin Golovine, Peter Makhov, Sei Naito, Henish Raiyani, Jeffrey Tomaszewski, Reza Mehrazin, Alexei Tulin, Alexander Kutikov, Robert G. Uzzo, Vladimir M. Kolenko

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)743-749
Number of pages7
JournalCancer Biology and Therapy
Volume16
Issue number5
DOIs
StatePublished - 1 Jan 2015
Externally publishedYes

Keywords

  • Cancer
  • Piperlongumine
  • ROS
  • Renal
  • c-Met

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