Parthenolide inhibits proliferation and invasion, promotes apoptosis, and reverts the cell–cell adhesion loss through downregulation of NF‐κB pathway TNF‐α‐activated in colorectal cancer cells

Abstract

AbstractThe activation of the nuclear factor‐κB (NF‐κB) pathway has been associated with the development and progression of colorectal cancer (CRC). Parthenolide (PTL), a well‐known inhibitor of the NF‐κB pathway, has emerged as an alternative treatment. However, whether PTL activity is tumor cell‐specific and dependent on the mutational background has not been defined. This study investigated the antitumor role of PTL after tumor necrosis factor‐α (TNF‐α) stimulation in various CRC cell lines with different mutational statuses of TP53. We observed that CRC cells displayed different patterns of basal p‐IκBα levels; PTL reduced cell viability according to p‐IκBα levels and p‐IκBα levels varied among the cell lines according to the time of TNF‐α stimulation. High concentrations of PTL reduced more effectively p‐IκBα levels than low doses of PTL. However, PTL increased total IκBα levels in Caco‐2 and HT‐29 cells. In addition, PTL treatment downregulated p‐p65 levels in HT‐29 and HCT‐116 cells stimulated by TNF‐α in a dose‐dependent manner. Moreover, PTL induced cell death via apoptosis and reduced the proliferation rate of TNF‐α‐treated HT‐29 cells. Finally, PTL downregulated the messenger RNA levels of interleukin‐1β, a downstream cytokine of NF‐κB, reverted the E‐cadherin‐mediated disorganization of cell–cell contacts, and decreased the invasion of HT‐29 cells. Together, these results suggest a differential antitumoral activity of PTL on CRC cells with different mutational statuses of TP53, modulating cell death, survival, and proliferation underlying the NF‐κB pathway TNF‐α‐induced. Therefore, PTL has emerged as a potential treatment for CRC in an inflammatory NF‐κB‐dependent manner.