Inhibition of protein kinase C delta leads to cellular senescence to induce anti‐tumor effects in colorectal cancer

Author:

Shimoyama Yuya1,Yamada Kohji1ORCID,Yoshida Saishu1,Kawamura Akira1,Hannya Yoshito1,Imaizumi Yuta2,Kumamoto Tomotaka2,Takeda Yasuhiro2,Shimoda Masayuki3,Eto Ken2,Yoshida Kiyotsugu1ORCID

Affiliation:

1. Department of Biochemistry The Jikei University School of Medicine Tokyo Japan

2. Department of Surgery The Jikei University School of Medicine Tokyo Japan

3. Department of Pathology The Jikei University School of Medicine Tokyo Japan

Abstract

AbstractProtein kinase C delta (PKCδ) is a multifunctional serine–threonine kinase implicated in cell proliferation, differentiation, tumorigenesis, and therapeutic resistance. However, the molecular mechanism of PKCδ in colorectal cancer (CRC) remains unclear. In this study, we showed that PKCδ acts as a negative regulator of cellular senescence in p53 wild‐type (wt‐p53) CRC. Immunohistochemical analysis revealed that PKCδ levels in human CRC tissues were higher than those in the surrounding normal tissues. Deletion studies have shown that cell proliferation and tumorigenesis in wt‐p53 CRC is sensitive to PKCδ expression. We found that PKCδ activates p21 via a p53‐independent pathway and that PKCδ‐kinase activity is essential for p21 activity. In addition, both repression of PKCδ expression and inhibition of PKCδ activity induced cellular senescence‐like phenotypes, including increased senescence‐associated β‐galactosidase (SA‐β‐gal) staining, low LaminB1 expression, large nucleus size, and senescence‐associated secretory phenotype (SASP) detection. Finally, a kinase inhibitor of PKCδ suppressed senescence‐dependent tumorigenicity in a dose‐dependent manner. These results offer a mechanistic insight into CRC survival and tumorigenesis. In addition, a novel therapeutic strategy for wt‐p53 CRC is proposed.

Funder

Japan Society for the Promotion of Science

Publisher

Wiley

Subject

Cancer Research,Oncology,General Medicine

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