Parthenolide inhibits proliferation and invasion, promotes apoptosis, and reverts the cell-cell adhesion loss through downregulation of NF-kappa B pathway TNF-alpha-activated in colorectal cancer cells

The activation of the nuclear factor-kappa B (NF-kappa B) pathway has been associated with the development and progression of colorectal cancer (CRC). Parthenolide (PTL), a well-known inhibitor of the NF-kappa B 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-alpha (TNF-alpha) stimulation in various CRC cell lines with different mutational statuses of TP53. We observed that CRC cells displayed different patterns of basal p-I kappa B alpha levels; PTL reduced cell viability according to p-I kappa B alpha levels and p-I kappa B alpha levels varied among the cell lines according to the time of TNF-alpha stimulation. High concentrations of PTL reduced more effectively p-I kappa B alpha levels than low doses of PTL. However, PTL increased total I kappa B alpha 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-alpha in a dose-dependent manner. Moreover, PTL induced cell death via apoptosis and reduced the proliferation rate of TNF-alpha-treated HT-29 cells. Finally, PTL downregulated the messenger RNA levels of interleukin-1 beta, a downstream cytokine of NF-kappa B, 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-kappa B pathway TNF-alpha-induced. Therefore, PTL has emerged as a potential treatment for CRC in an inflammatory NF-kappa B-dependent manner.