Abstract 5742: p38 MAPK functions as a tumor suppressor in skin epithelial cells, but as a tumor promoter in myeloid cells

Abstract

Abstract The p38 MAP kinase plays a pivotal role in cellular responses to stress, mitogenic stimuli and immune signaling. Evidence from clinical observations and cell culture experiments reveals a role for p38 in many aspects of cancer and immunity. Meanwhile, attempts to determine the physiological role of p38 in mice have been hampered due to the early embryonic lethality of mice null for p38alpha, the most abundant and ubiquitously expressed p38 isoform. To overcome this challenge, we generated conditional knockout mice in which p38alpha expression was specifically ablated in epithelial cells and immune cells, and have discovered that p38alpha plays a crucial role in inflammation and immune response in a cell type-dependent manner. Here, we investigated the role of p38alpha in keratinocytes and myeloid cells in a chemically induced skin carcinogenesis model. Our study using conditional knockout animals showed that keratinocyte- and myeloid-specific p38α ablation resulted in an increase and decrease, respectively, in tumor incidence. Furthermore, tumors from the two groups of mutant mice displayed contrasting histological features in the intratumoral and tumor-stromal areas. Interestingly, tumors derived from p38alpha-deficient keratinocytes highly expressed p63 positive stem cell populations. High p63 expression was also detected in p38alpha-deficient epidermis in adult skin. p38alpha-ablated epidermis harbored greater numbers of colony-forming cells and side population cells. Mechanistically, we discovered that p38alpha directly phosphorylated and thereby destabilized p63. We identified the amino acid residues on p63 that were directly phosphorylated by p38alpha in vivo and in vitro. p63 phosphorylation by p38alpha contributed to shaping keratinocyte gene expression related to stem cell homeostasis, inflammation, and tumorigenesis. These findings illustrate a novel link between stress-induced protein kinase signaling and p63-dependent epidermal homeostasis. On the other hand, p38 ablation in macrophages upregulated chemokine expression to recruit cytotoxic T cells to tumor microenvironments and resulted in tumor regression. LPS-induced ATF3 expression was reduced in p38alpha-deficient mouse and human macrophages, and p38alpha-overexpression increased ATF3 level. According to the publicly available datasets, T cell-recruiting chemokine expression is upregulated in ATF3 KO macrophages. Therefore, ATF3 may link to p38alpha to chemokine expression in macrophages. These data suggest that p38alpha in epithelial cells and myeloid cells plays a distinct role in skin tumorigenesis and cell type-specific targeting should be considered to increase drug efficacy and reduce adverse effects. Citation Format: Min-Kyung Choo, Jin Mo Park. p38 MAPK functions as a tumor suppressor in skin epithelial cells, but as a tumor promoter in myeloid cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5742.