Protein kinase C downregulation induces senescence via FoxO3a inhibition in HCT116 and HEK293 cells
We investigated the impact of protein kinase C (PKC) on cellular senescence. The PKC activity and expression of conventional PKC (cPKC) and atypical PKC (aPKC) isoforms decreased during replicative senescence in IMR-90 cells. Forced inhibition of cPKC or aPKC induced the activation of senescence markers, including senescence-associated β-galactosidase activity and reactive oxygen species (ROS)-p53-p21{sup Cip1/WAF1} axis in HCT116 and HEK293 cells. PKC inhibition triggered the nuclear exportation of FoxO3a via stimulation of AKT-mediated phosphorylation of FoxO3a, and thereby decreased the transcription of FoxO3a target genes. Conversely, ectopic expression of the PKC isoforms led to stimulation of the nuclear import of FoxO3a and expression of the FoxO3a target genes. Ectopic FoxO3a expression attenuated ROS accumulation and senescent phenotypes induced by PKC inhibition. Therefore, this study suggests for the first time that downregulation of PKC induces senescence through the AKT-FoxO3a-ROS-p53-p21{sup Cip1/WAF1} pathway in HCT116 and HEK293 cells. - Highlights: • The activity and expression of PKC decreased during replicative senescence. • PKC downregulation induced senescence markers and ROS production. • PKC downregulation induced nuclear export of FoxO3a via AKT activation. • PKC downregulation reduced transcription of anti-oxidant genes. • PKC downregulation induces senescence via the AKT-FoxO3a-ROS pathway.
- OSTI ID:
- 22719149
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 493, Issue 4; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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