Reverse phase protein array identifies novel anti-invasion mechanisms of YC-1

Biochem Pharmacol. 2010 Mar 15;79(6):842-52. doi: 10.1016/j.bcp.2009.10.021. Epub 2009 Oct 30.

Abstract

YC-1 has recently been demonstrated to have potent anti-invasion and anti-metastatic activity in several cancer models, in addition to its anti-proliferation activity. However, the mechanism underlying its anti-invasion/anti-metastatic activity is largely unknown. Nasopharyngeal carcinoma (NPC) is a highly metastatic head and neck cancer in Southeast Asia. Here, we demonstrated that YC-1 inhibited invasiveness and proliferation of NPC cells, with the latter being accompanied by PARP cleavage, S-phase arrest and activation of Chk1/Chk2. We aimed at identifying novel anti-invasion mechanisms of YC-1 in NPC by a functional proteomic platform, the reverse phase protein array (RPPA). Our study revealed for the first time that multiple invasion-related signaling proteins (beta-catenin, caveolin, Src and EGFR), as well as several growth-related proteins (AMPKalpha, phospho-acetyl-CoA carboxylase (p-ACC), HER-2 and mTOR), which were previously un-described signaling proteins altered by YC-1, were found to be down-modulated by YC-1 in NPC cells. We hypothesized that YC-1-mediated downregulation of these invasion proteins contributed to its anti-invasion activity in NPC cells. Overexpression of EGFR, activated Src or caveolin, but not beta-catenin reversed the inhibitory effects of YC-1 on NPC cell invasion, with EGFR and activated Src having additional effects on rescuing NPC cells from YC-1-mediated growth inhibition. In summary, we have identified several novel anti-invasion mechanisms of YC-1 that could impact NPC, and possibly other cancers as well.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Carcinoma / drug therapy
  • Carcinoma / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Checkpoint Kinase 1
  • Checkpoint Kinase 2
  • Down-Regulation
  • Furans / pharmacology*
  • Gene Expression Regulation, Neoplastic / physiology
  • Humans
  • Indazoles / pharmacology*
  • Nasopharyngeal Neoplasms / drug therapy
  • Nasopharyngeal Neoplasms / pathology
  • Neoplasm Invasiveness
  • Neoplasm Proteins / metabolism*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Protein Array Analysis / methods*
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • S Phase / drug effects

Substances

  • Antineoplastic Agents
  • Furans
  • Indazoles
  • Neoplasm Proteins
  • 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole
  • Poly(ADP-ribose) Polymerases
  • Protein Kinases
  • Checkpoint Kinase 2
  • CHEK1 protein, human
  • CHEK2 protein, human
  • Checkpoint Kinase 1
  • Protein-Serine-Threonine Kinases