|Randhawa, Harsharan -|
|Kibble, Kendra -|
|Mayer, Mary -|
|Reindl, Katie -|
Submitted to: Toxicology In Vitro
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: April 2, 2013
Publication Date: April 18, 2013
Repository URL: http://handle.nal.usda.gov/10113/56677
Citation: Randhawa, H., Kibble, K., Zeng, H., Mayer, M.P., Reindl, K.M. 2013. Activation of ERK signaling and induction of colon cancer cell death by piperlongumine. Toxicology In Vitro. 27:1626-1633. Interpretive Summary: Piperlongumine (PPLGM) is a natural product constituent of the fruit of the Long pepper (Piper longum), a pepper plant found in southern India and southeast Asia. PPLGM may have anti-cancer properties. For example, in mice injected with human bladder, breast, lung, colon or melanoma cancer cells, PPLGM inhibited tumor growth but showed no toxicity in normal mice. It selectively targets and kills cancer cells but leaving normal cells unharmed. However, the mechanism by which that PPLGM selectively induces colon cancer cells but not normal colon cells remains largely unknown. A more thorough understanding of the mechanisms will be useful in developing nutritional/ therapeutic strategies to prevent/treat colon cancer. We found that, in vitro, 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 through a cell proliferation kinase pathway which is extracellular-signal-regulated kinase (ERK). This cell proliferation pathway (ERK) may provide for molecular targets for future nutritional and/or therapeutic in vivo study. The information will be useful for scientists and health-care professionals who are interested in nutrient and cancer prevention.
Technical 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 minutes) and prolonged (24 hours) 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 2 mechanisms by which PPLGM induces colon cancer cell death will be useful in developing therapeutic strategies to treat colon cancer.