Protein kinase D1 is essential for Ras-induced senescence and tumor suppression by regulating senescence-associated inflammation

Abstract

Oncogene-induced senescence (OIS) is an initial barrier to tumor development. Reactive oxygen species (ROS) is critical for onco-genic Ras OIS, but the downstream effectors to mediate ROS signaling are still relatively elusive. Senescent cells develop a senescence-associated secretory phenotype (SASP). However, the mechanisms underlying the regulation of the SASP are largely unknown. Here, we identify protein kinase D1 (PKD1) as a downstream effec-torof ROS signaling to mediate Ras OIS and SASP. PKD1 is activated by oncogenic Ras expression and PKD1 promotes Ras OIS by mediating inflammatory cytokines interleukin-6 (IL-6) and interleukin-8 (IL-8) via modulation of NF-κB activity. We demonstrate that ROSprotein kinaseCδ(PKCδ)- PKD1 axisisessential for the establishment and maintenance of IL-6/IL8 induction. In addition, ablationof PKD1 causes the bypass of Ras OIS, and promotes cell transformation and tumorigenesis. Together, these findings uncover a previously unidentified role of ROS-PKCδ-PKD1 pathway in Ras OIS and SASP regulation.