Cutaneous squamous cell carcinoma (CSCC), the most aggressive non-melanoma skin cancer, is the second most common cancer in the USA and worldwide. Head and neck SCC (HNSCC) is a leading cause of cancer deaths worldwide and accounts for 3-5% of all cancers in USA. Together, these cancers (SCC) contribute substantially to morbidity and mortality. Our long-term goal is to develop novel approaches to SCC prevention and treatment based on a deep understanding of its pathogenesis. The specific goal of this application is to define a novel tumor suppressive role for alkaline ceramidase 1 (ACER1), a member in the alkaline ceramidase family that we identified initially from the yeast Saccharomyces cerevisiae and then from mammals, in SCC development and progression. SCC arises from keratinocytes or squamous cells through a multistage process including tumor promotion. Tumor promotion alters the expression of genes controlling cell proliferation, differentiation, and apoptosis and identification of such genes offers targets for chemoprevention and/or therapy. Through gene expression profiling, we find that 12-O-tetradecanoylphorbol-13-acetate (TPA), the classic tumor promoter, inhibits the expression of ACER1 in normal epidermal keratinocytes. Importantly, we demonstrate that overexpression of the human ACER1 transgene in the mouse epidermis increases tumor latency and reduces tumor burden in the two-stage skin carcinogenesis model initiated with 7,12- dimethylbenz(a)anthracene (DMBA) and promoted with TPA, suggesting that ACER1 downregulation contributes to tumor promotion. Consistent with this notion, we show that ACER1 expression is markedly suppressed in SCC cell lines and tissues and that restoring ACER1 expression inhibits the proliferation of SCC cells, suggesting that ACER1 downregulation leads to the hyperproliferation of premalignant and malignant keratinocytes, thereby promoting SCC development. Based on these important findings, we hypothesize that ACER1 acts as a tumor suppressor in SCC and that its downregulation promotes skin tumorigenesis by promoting epidermal keratinocyte hyperproliferation. As a further corollary, we hypothesize that rectifying the ACER1 mediated pathway will inhibit skin tumorigenesis. These hypotheses will be tested by two specific aims.
In Aim 1, we will define the tumor suppressive role for ACER1 in SCC using both in vitro model of tumor promotion and animal models of skin tumorigenesis and establish that dysregulation of the ACER1/sphingolipid pathway is a predictive biomarker for early onset SCC.
In Aim 2 we will define the cellular and molecular mechanisms by which the ACER1/sphingolipid pathway functions as a tumor suppressor in SCC. The proposed research will provide not only insights into the role of the ACER1/sphingolipid pathway in SCC suppression but also an intellectual framework for skin cancer prevention and treatment.

Public Health Relevance

More than 1 million cases of skin cancer and 49,00 cases of head and neck cancer are diagnosed annually within the United States. As such, there is a critical need to develop preventive measures and therapeutic approaches to combat these diseases. The PI's laboratory has identified a novel enzyme called the alkaline ceramidase 1 (ACER1) that regulates sphingolipids (a type of lipids) and may function as a tumor suppressor in skin and head and neck cancer. This application is to understand the tumor suppressive role for ACER1 and its lipid mediator in inhibiting tumorigenesis and the underlying mechanism for their anti-cancer action. Completion of studies proposed in this application may provide important molecular bases for the prevention and treatment of skin cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA097132-11A1
Application #
8742660
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (M1))
Project Start
2002-07-01
Project End
2019-08-31
Budget Start
2014-09-22
Budget End
2015-08-31
Support Year
11
Fiscal Year
2014
Total Cost
$215,398
Indirect Cost
$77,433
Name
State University New York Stony Brook
Department
Type
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Lu, Songjian; Cai, Chunhui; Yan, Gonghong et al. (2016) Signal-Oriented Pathway Analyses Reveal a Signaling Complex as a Synthetic Lethal Target for p53 Mutations. Cancer Res 76:6785-6794
Carroll, Brittany L; Pulkoski-Gross, Michael J; Hannun, Yusuf A et al. (2016) CHK1 regulates NF-κB signaling upon DNA damage in p53- deficient cells and associated tumor-derived microvesicles. Oncotarget 7:18159-70
Xu, Ruijuan; Wang, Kai; Mileva, Izolda et al. (2016) Alkaline ceramidase 2 and its bioactive product sphingosine are novel regulators of the DNA damage response. Oncotarget 7:18440-57
García-Barros, Mónica; Coant, Nicolas; Kawamori, Toshihiko et al. (2016) Role of neutral ceramidase in colon cancer. FASEB J 30:4159-4171
McCracken, A N; McMonigle, R J; Tessier, J et al. (2016) Phosphorylation of a constrained azacyclic FTY720 analog enhances anti-leukemic activity without inducing S1P receptor activation. Leukemia :
Adada, Mohamad; Luberto, Chiara; Canals, Daniel (2016) Inhibitors of the sphingomyelin cycle: Sphingomyelin synthases and sphingomyelinases. Chem Phys Lipids 197:45-59
Espaillat, Mel Pilar; Kew, Richard R; Obeid, Lina M (2016) Sphingolipids in neutrophil function and inflammatory responses: Mechanisms and implications for intestinal immunity and inflammation in ulcerative colitis. Adv Biol Regul :
Wang, K; Xu, R; Snider, A J et al. (2016) Alkaline ceramidase 3 deficiency aggravates colitis and colitis-associated tumorigenesis in mice by hyperactivating the innate immune system. Cell Death Dis 7:e2124
Kitatani, K; Usui, T; Sriraman, S K et al. (2016) Ceramide limits phosphatidylinositol-3-kinase C2β-controlled cell motility in ovarian cancer: potential of ceramide as a metastasis-suppressor lipid. Oncogene 35:2801-12
Wu, Song; Powers, Scott; Zhu, Wei et al. (2016) Substantial contribution of extrinsic risk factors to cancer development. Nature 529:43-7

Showing the most recent 10 out of 172 publications