Activation of ERK signaling and induction of colon cancer cell death by piperlongumine

Toxicol In Vitro. 2013 Sep;27(6):1626-33. doi: 10.1016/j.tiv.2013.04.006. Epub 2013 Apr 18.

Abstract

Piperlongumine (PPLGM) is a bioactive compound isolated from long peppers that shows selective toxicity towards a variety of cancer cell types including colon cancer. The signaling pathways that lead to cancer cell death in response to PPLGM exposure have not been previously identified. Our objective was to identify the intracellular signaling mechanisms by which PPLGM leads to enhanced colon cancer cell death. We found that PPLGM inhibited the growth of colon cancer cells in time- and concentration-dependent manners, but was not toxic toward normal colon mucosal cells at concentrations below 10 μM. Acute (0-60 min) and prolonged (24h) exposure of HT-29 cells to PPLGM resulted in phosphorylation of ERK. To investigate whether ERK signaling was involved in PPLGM-mediated cell death, we treated HT-29 cells with the MEK inhibitor U0126, prior to treating with PPLGM. We found that U0126 attenuated PPLGM-induced activation of ERK and partially protected against PPLGM-induced cell death. These results suggest that PPLGM works, at least in part, through the MEK/ERK pathway to result in colon cancer cell death. A more thorough understanding of the molecular mechanisms by which PPLGM induces colon cancer cell death will be useful in developing therapeutic strategies to treat colon cancer.

Keywords: Apoptosis; Cell signaling; Colon cancer; ERK; MAPK; MEK; MEK/ERK; PPLGM; Piperlongumine; RAS; ROS; extracellular-signal-regulated kinase; mitogen-activated protein kinase; piperlongumine; rat sarcoma oncogene; reactive oxygen species.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line
  • Colon / cytology
  • Colonic Neoplasms / metabolism*
  • Dioxolanes / pharmacology*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Intestinal Mucosa / cytology
  • MAP Kinase Signaling System / drug effects*
  • Signal Transduction / drug effects

Substances

  • Antineoplastic Agents
  • Dioxolanes
  • Extracellular Signal-Regulated MAP Kinases
  • piperlonguminine