Type I interferon prolongs cell cycle progression via p21WAF1/CIP1 induction in human colon cancer cells

Abstract

Type I interferon (IFN) was originally identified as an immunomodulatory cytokine because of its antiviral activity. Further characterization of its biological effects revealed a prominent role in the direct control of cell growth and potent immunomodulatory and antiangiogenic actions. IFN-α and IFN-ß had both been classified as type I IFN, but differences in their antitumor activities were reported. We confirmed the difference in the antiproliferative activities of IFN-α2b and IFN-ß toward HT29 and SW480 cells. IFN treatment was observed to prolong cell cycle progression; in particular, the accumulation of S-phase population was one of the most characteristic changes. The prolongation of S-phase progression and transition into G2/M-phase was suggested to be a crucial action of type I IFN on colon cancer. Additionally, IFN activated the p21 promoter gene and induced p21 WAF1/CIP1 expression. Furthermore, the cell cycle prolongation effect of IFN was suppressed when p21 expression was downregulated. Therefore, we confirmed that p21 WAF1/CIP1 was a crucial target molecule for the effects of IFN on the cell cycle. Additionally, the ability of p21 induction differed between IFN-α2b and IFN-ß and correlated with their inhibitory activities toward cell growth. We conclude that type I IFN prolongs cell cycle progression by p21 WAF1/CIP1 induction in human colon cancer cells.

Regulatory Effects of Programmed Cell Death 4 (PDCD4) Protein in Interferon (IFN)-Stimulated Gene Expression and Generation of Type I IFN Responses

“…6A). This stabilization of PDCD4 protein correlated with suppression of induction of gene products with important roles in the generation of the biological effects of IFNs, including ISG15 (58), p21 WAF1/CIP1 (17), and SLFN5 (18) (Fig. 6A).…”

Blocking Interferon β Stimulates Vascular Smooth Muscle Cell Proliferation and Arteriogenesis

“…The cell cycle regulator p21 is known as the major mediator of cell cycle arrest (13). Its regulation by IFN␤ has previously been observed in tumor cells (14), and inhibition of p21 has been shown to regulate endothelial cell proliferation (15). Antiproliferative, pro-apoptotic effects of IFN␤ are known in oncology but have not yet been examined in cardiovascular pathophysiology.…”

Type-I-interferons in infection and cancer: Unanticipated dynamics with therapeutic implications

“…55 More recently, Katayama and colleagues provided evidence that, in human colon cancer cells, the antiproliferative action of Type-I-IFNs relied on a p21-dependent prolongation of the S phase rather than a G 1 block. 56 Yet other nets involved in Type-I-IFN-induced cell-cycle arrest are believed to include the downregulation of the transcription factor MYC and the activation of mitogen-activated protein kinase (MAPK)14 or the adapter molecule CRK. 57,58 Contrasting experimental findings indicate that Type-I-IFNs can either induce tumor cell death 59 or protect cancer cells from chemical-induced apoptosis 60 (panels 2 and 5, Fig.…”