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

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 mechanisms by which PPLGM induces colon cancer cell death will be useful in developing therapeutic strategies to treat colon cancer.

Transcriptome Analysis of Piperlongumine-Treated Human Pancreatic Cancer Cells Reveals Involvement of Oxidative Stress and Endoplasmic Reticulum Stress Pathways

“…PL also modulated the expression of many cell signaling molecules, such as mitogenactivated protein kinases in the pancreatic cancer cells, which is in support of previous studies showing that PL modulates cell signaling pathways to lead to enhanced cancer cell death. 23,25,26 Not surprisingly, the RNA-seq data revealed that PL triggers an oxidative stress response in pancreatic cancer cells. What was interesting was the identification of new genes likely involved in this response.…”

Piperlongumine Chemosensitizes Tumor Cells through Interaction with Cysteine 179 of IκBα Kinase, Leading to Suppression of NF-κB–Regulated Gene Products

“…Piperlongumine has multiple pharmacologic activities: it has been described as a platelet aggregation inhibitor (3), an anxiolytic agent (4), an antidepressant (5), an antinociceptive agent (6), an anti-atherosclerotic agent (7), an antidiabetic agent (8), an anti-inflammatory agent (9), and an infectious pathogen inhibitor (10). Furthermore, piperlongumine has been reported to kill multiple types of cancer cells, inhibit metastasis, and have antitumor activities in a variety of animal models (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).…”

“…How piperlongumine acts as an anticancer agent is not yet clear. Several studies have demonstrated that it induces cytotoxicity through a variety of mechanisms, such as activation of caspases (14,20,21), activation of the ERK pathway (11), inhibition of cdc-2, cdk2, and cyclin D1 (19, B, dose-dependent effect of piperlongumine on TNFa-induced NF-kB activation. KBM-5 cells were treated with the indicated concentrations of piperlongumine for 4 hours and then exposed to 0.1 nmol/L TNFa for 30 minutes.…”

Piperlongumine Suppresses Growth and Sensitizes Pancreatic Tumors to Gemcitabine in a Xenograft Mouse Model by Modulating the NF-kappa B Pathway

“…Among the multivalent effects, the potential of piperlongumine as a novel anticancer agent have gained considerable attention recently. Emerging evidence suggests that piperlongumine is capable of killing multiple types of cancer cells, including Burkitt lymphoma (25), head and neck cancer (26), ovarian cancer (27), glioblastoma multiforme (28), breast cancer (29), prostate cancer (30), and colon cancer (31). This alkaloid was also found to sensitize tumors to chemotherapeutic agents such as cisplatin and paclitaxel (26,27).…”

“…The antitumor effect of piperlongumine may be associated with its ability to target the cellular stress response through direct inhibition of Glutathione S-transferase pi 1 (GSTP1; ref. 33), activate ERK signaling (31,35), target p38 signaling (36), suppress STAT3 phosphorylation (34), generate reactive oxygen species (ROS; Figure 1. Piperlongumine suppresses the proliferation and potentiates the apoptotic effects of gemcitabine in pancreatic cancer cells in vitro.…”