Piperlongumine Inhibits Migration of Glioblastoma Cells via Activation of ROS-Dependent p38 and JNK Signaling Pathways

Abstract

Piperlongumine (PL) is recently found to kill cancer cells selectively and effectively via targeting reactive oxygen species (ROS) responses. To further explore the therapeutic effects of PL in cancers, we investigated the role and mechanisms of PL in cancer cell migration. PL effectively inhibited the migration of human glioma (LN229 or U87 MG) cells but not normal astrocytes in the scratch-wound culture model. PL did not alter EdU+-cells and cdc2, cdc25c, or cyclin D1 expression in our model. PL increased ROS (measured by DCFH-DA), reduced glutathione, activated p38 and JNK, increased IκBα, and suppressed NFκB in LN229 cells after scratching. All the biological effects of PL in scratched LN229 cells were completely abolished by the antioxidant N-acetyl-L-cysteine (NAC). Pharmacological administration of specific p38 (SB203580) or JNK (SP600125) inhibitors significantly reduced the inhibitory effects of PL on LN229 cell migration and NFκB activity in scratch-wound and/or transwell models. PL prevented the deformation of migrated LN229 cells while NAC, SB203580, or SP600125 reversed PL-induced morphological changes of migrated cells. These results suggest potential therapeutic effects of PL in the treatment and prevention of highly malignant tumors such as glioblastoma multiforme (GBM) in the brain by suppressing tumor invasion and metastasis.

Piperlongumine selectively kills hepatocellular carcinoma cells and preferentially inhibits their invasion via ROS-ER-MAPKs-CHOP

“…Different from previous studies which showed a differentially activation of p38, JNK and Erk in distinct cancer cells [9,10,15], we demonstrated that PL induced prominent activation of all the three major MAPKs signaling pathways including p38, JNK and Erk in HCC cells, supporting that MAPKs were major ROS-stress responsive signaling pathways upon PL treatment. It is well-known that ER is a major organelle responsible for ROS accumulation [20] and MAPKs are canonical downstream signaling pathways of ER stress-responses [21].…”

“…Interestingly, suppressing ER-MAPKs-CHOP signaling axis by either inhibitors (4-PBA, SP, SB, or U0126) or knocking-down of CHOP did not affect the rate of HCC cell death evidently but showed prominent effects on HCC cell migration, suggesting that PL preferentially suppressed HCC migration/invasion via ER-MAPKs-CHOP. Consistent with PL's effects on HCC cell migration, PL also suppresses cell migration of highly malignant GBM cells via ROS-p38/JNK/NFκB signaling [10]. These evidences suggest that MAPKs might be a signaling hub for PL's suppressed effects on cell migration/invasion.…”

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

“…7 Previous studies have shown that PL selectively kills a variety of cancer cell lines with minimal death for normal cells by elevating ROS levels and inducing apoptosis. 8 Additionally, PL has been shown to cause cell cycle arrest, 9 induce autophagy, 10 and inhibit migration, 11 adhesion, and invasion. 12 While multiple studies have reported the cancer-specific cytotoxicity of PL, the gene expression profile and pathways associated with PL-mediated anticancer effects have not been fully elucidated, particularly for pancreatic cancer.…”

Piperlongumine induces apoptotic and autophagic death of the primary myeloid leukemia cells from patients via activation of ROS-p38/JNK pathways

“…Recently, the anticancer effects of PL have been demonstrated in more cancer cell lines, and multiple mechanisms have been proposed to explain the activity of PL, including the induction of apoptosis [12] , autophagic cell death [13] or cell-cycle arrest [14] . The downstream signaling pathways activated by ROS accumulation in cancer cells include the p38 mitogen-activated protein kinase (p38 MAPK) pathway, the c-Jun N-terminal kinase (JNK) pathway, the extracellular signal-regulated kinase (Erk) pathway and the nuclear factor κB (NFκB) pathway [12,[15][16][17] . Previous studies examined only the cytotoxic effects of PL in cancer cell lines.…”