Abstract
Simple SummaryThere are a number of reports in the scientific literature dealing with the implication of ceramide kinase (CERK) and its product, ceramide 1-phosphate (C1P), in the regulation of cell growth and survival, apoptosis, inflammation, and cell migration/invasion. However, no report has so far compiled or put into context the information related to the implication of the CERK/C1P axis in cancer development and metastasis. Hence, the present review highlights the relevance of CERK and C1P in tumorigenesis and tumor dissemination. Whilst CERK produces intracellular C1P, which can act on intracellular targets directly, C1P can also be secreted into the extracellular milieu and interact with sites (possibly receptors) at the plasma membrane of cells. This action can trigger signaling cascades that may end up modulating the expression of specific genes involved in tumor promotion and dissemination. The biology of CERK/C1P in cancer growth and dissemination is herein discussed in detail.Cancer cells rewire their metabolic programs to favor biological processes that promote cell survival, proliferation, and dissemination. Among this relevant reprogramming, sphingolipid metabolism provides metabolites that can favor or oppose these hallmarks of cancer. The sphingolipid ceramide 1-phosphate (C1P) and the enzyme responsible for its biosynthesis, ceramide kinase (CERK), are well established regulators of cell growth and survival in normal, as well as malignant cells through stress-regulated signaling pathways. This metabolite also promotes cell survival, which has been associated with the feedback regulation of other antitumoral sphingolipids or second messengers. C1P also regulates cancer cell invasion and migration of different types of cancer, including lung, breast, pancreas, prostate, or leukemia cells. More recently, CERK and C1P have been implicated in the control of inflammatory responses. The present review provides an updated view on the important role of CERK/C1P in the regulation of cancer cell growth, survival, and dissemination.
Highlights
Ceramide kinase (CERK) was first discovered in rat neural secretory vesicles by S
It is well established that C1P and ceramide kinase (CERK) regulate cell growth, survival, and motility in both malignant and non-malignant cells
CERK/C1P exerts its biological functions are still incomplete, accumulating evidence supports the notion that this enzyme activity and its product are relevant targets for reducing tumor formation and spreading
Summary
Ceramide kinase (CERK) was first discovered in rat neural secretory (synaptic) vesicles by S. The increased migration of CERK-overexpressing cells was reduced by pretreatment of the cells with the CERK inhibitor NVP-231 or by knocking down CERK expression with specific short hairpin RNAs. inhibition of the PI3K/Akt pathway or RhoA-dependent protein kinase (ROCK) with the selective inhibitors LY290042 or Y27632, respectively, blocked migration of CERK-overexpressing breast cancer cells, suggesting a relevant role of these pathways in the regulation of CERK-associated breast cancer cell migration; targeting this enzyme may be an important therapeutic strategy in metastatic breast cancer. CERK inhibition using NVP-231 blocked breast and lung cancer cell proliferation by inducing M phase arrest and subsequent cell death [44].
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