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

• Published in: Toxicology in vitro Vol. 27; no. 6; pp. 1626 - 1633
• Main Authors: Randhawa, H., Kibble, K., Zeng, H., Moyer, M.P., Reindl, K.M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.09.2013
• Subjects: anticarcinogenic activity; antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; cell death; Cell Line; Cell signaling; colon; Colon - cytology; Colon cancer; Colonic Neoplasms - metabolism; colorectal neoplasms; Dioxolanes - pharmacology; dose response; Extracellular Signal-Regulated MAP Kinases - metabolism; HCT116 Cells; HT29 Cells; Humans; intestinal mucosa; Intestinal Mucosa - cytology; MAP Kinase Signaling System - drug effects; MEK/ERK; mitogen-activated protein kinase; Piper longum; Piperlongumine; protein phosphorylation; Signal Transduction - drug effects; toxicity; Piperlongumine; MEK; Colon cancer; RAS; ROS; MEK/ERK; MAPK; PPLGM; Cell signaling; ERK; Apoptosis; extracellular-signal-regulated kinase; mitogen-activated protein kinase; rat sarcoma oncogene; reactive oxygen species
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2013.04.006

•PPLGM inhibits colon cancer cell proliferation and induces apoptosis.•PPLGM activates ERK signaling.•Inhibition of ERK signaling reduces PPLGM-induced colon cancer cell death. 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 10μM. Acute (0–60min) 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.