title: 5-Fluorouracil-induced apoptosis in colorectal cancer cells is caspase-9-dependent and mediated by activation of protein kinase C-δ
abstract: Elucidation of the molecular mechanisms by which 5-fluorouracil (5-FU) induces apoptosis is required in order to understand the resistance of colorectal cancer (CRC) cells to 5-FU. In the current study, 5-FU-induced apoptosis was assessed using the propidium iodide method. Involvement of protein kinase C (PKC) was assessed by evaluating the extent of their activation in CRC, following treatment with 5-FU, using biochemical inhibitors and western blot analysis. The results revealed that 5-FU induces varying degrees of apoptosis in CRC cells; HCT116 cells were identified to be the most sensitive cells and SW480 were the least sensitive. In addition, 5-FU-induced apoptosis was caspase-dependent as it appeared to be initiated by caspase-9. Furthermore, PKCɛ was marginally expressed in CRC cells and no changes were observed in the levels of cleavage or phosphorylation following treatment with 5-FU. The treatment of HCT116 cells with 5-FU increased the expression, phosphorylation and cleavage of PKCδ. The inhibition of PKCδ was found to significantly inhibit 5-FU-induced apoptosis. These results indicated that 5-FU induces apoptosis in CRC by the activation of PKCδ and caspase-9. In addition, the levels of PKCδ activation may determine the sensitivity of CRC to 5-FU.
authors.affiliation: Department of Clinical Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan.
authors.forename: Nizar M
authors.initials: NM
authors.lastname: Mhaidat
authors.affiliation: Department of Clinical Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Bouklihacene
authors.affiliation: Department of Cancer Research Unit, Newcastle University, Newcastle, NSW 2300, Australia.
authors.forename: Rick F
authors.initials: RF
authors.lastname: Thorne
keywords: 5-fluorouracil; apoptosis; colorectal cancer; protein kinase C