Friday, November 22, 2024
11/22/2024
ABSTRACT Sphingolipid metabolites and their metabolic enzymes, often dysregulated in cancer, may present a novel but exploitable target for therapeutics against aggressive diseases such as triple -negative breast cancer (TNBC) and epidermal growth factor receptor 2 (HER2+) breast cancers, where new therapy is desperately needed. A growing body of evidence implicates the cellular bioactive sphingolipid metabolite, ceramide -1- phosphate (C1P), and ceramide kinase (CERK), the only mammalian enzyme known to produce cellul ar C1P, as essential signaling mediators of inflammation and cancer progression. However, the function of C1P and CERK remains enigmatic. Nevertheless, CERK is prominently associated with cancer, including lung adenocarcinoma, pancreatic cancer, and breast cancer. Excessive tumor CERK expression correlates with greater aggressiveness and poorer clinical outcome. A Cancer CERK is linked with activation of Ras/ERK, PI3K/AKT/mTOR, and resistance to chemotherapy. It is commonly thought that Golgi-resident CERK generates C1P that is released into the extracellular milieu and that signals through unknowncell surface G -protein coupled receptors to regulate inflammation and cancer cell survival, migration and wound healing. Challenging the notion of Golgi-resident CERK, our Preliminary Results showed enzymatically active CERK is enriched in the nucleus of normal breast epithelial cells and highly overexpressed in aggressive breast cancer cells. The presence of nuclear CERK and intracellular C1P implicate an undocumented underlying mechanism in aggressive breast cancer. Moreover, our Preliminary Data point to a previously uncharacterized role of CERK in aggressive diseases. 1.) Analysis of breast cancer metastases cohort (GSE2034, n=286) data revealed higher expression levels of CERK mRNA are linked to poor relapse-free survival (RFS). 2.) Our RNA-Seq data showed that CERK expression is elevated in primary breast tumors in patients with a history of breast cancer bone metastasis. 3.) As a proof-of-principle, an existing CERK inhibitor, NVP-231, drastically reduced the 3D invasive growth of aggressive breast cancer cells. 4.) NVP-231 also reduces aggressive type tumor progression and metastasis in mouse models. The overarching hypothesis is that CERK and C1P in the nucleus play a key role in aggressive breast cancer progression and metastasis. The immediate goal of this proposal is to gather more robust preliminary data to understand the functions, a) clinical utility and significance, and b) characterization of CERK and C1P in aggressive breast cancers. Two Specific Aims are proposed, 1) Clinical significance of ceramide kinase and C1P and 2) Functional role of ceramide kinase and C1P in aggressive breast cancers. The scope of the proposed work explores a previously unknown novel mechanism by which CERK and C1P function in the nucleus. This work will demonstrate whether nuclear C1P and CERK are critical for aggressive diseases for developing novel therapeutics, which can be tested for R01/DoD grant application.
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