Targeting Sphingosine 1-Phosphate Metabolism as a Therapeutic Avenue for Prostate Cancer

Abstract

Prostate cancer (PC) is the second most common cancer in men worldwide. More than 65% of men diagnosed with PC are above 65. Patients with localized PC show high long-term survival, however with the disease progression into a metastatic form, it becomes incurable, even after strong radio- and/or chemotherapy. Sphingosine 1-phosphate (S1P) is a bioactive lipid that participates in all the steps of oncogenesis including tumor cell proliferation, survival, migration, invasion, and metastatic spread. The S1P-producing enzymes sphingosine kinases 1 and 2 (SK1 and SK2), and the S1P degrading enzyme S1P lyase (SPL), have been shown to be highly implicated in the onset, development, and therapy resistance of PC during the last 20 years. In this review, the most important studies demonstrating the role of S1P and S1P metabolic partners in PC are discussed. The different in vitro, ex vivo, and in vivo models of PC that were used to demonstrate the implication of S1P metabolism are especially highlighted. Furthermore, the most efficient molecules targeting S1P metabolism that are under preclinical and clinical development for curing PC are summarized. Finally, the possibility of targeting S1P metabolism alone or combined with other therapies in the foreseeable future as an alternative option for PC patients is discussed. Research Strategy: PubMed from INSB was used for article research. First, key words “prostate & sphingosine” were used and 144 articles were found. We also realized other combinations of key words as “prostate cancer bone metastasis” and “prostate cancer treatment”. We used the most recent reviews to illustrate prostate cancer topic and sphingolipid metabolism overview topic.

The emerging roles of sphingosine 1-phosphate and SphK1 in cancer resistance: a promising therapeutic target

“…S1P signaling augments cancer cell proliferation, chemoresistance, and metastasis [ 107 , 108 ]. The elevation in S1P level was obtained in several cancers, including ovarian, prostate, colorectal, breast, and HCC [ 21 , 109 , 110 ]. HER2-positive breast cancer cells are characterized by high production of 17β-estradiol (E2) [ 111 ].…”

“…Then, S1P binds to its receptors and enhances the ERK1/2 pathway, which downregulates several machineries, including apoptosis and autophagy, promoting breast cancer cell growth, progression, and metastasis [ 111 ]. However, patients with breast cancer type ER-negative have higher concentrations of the enzyme SphK1, which is strongly associated with a high cancer proliferation rate and poor prognosis [ 21 ]. Conversely, breast cancer cells with ER-negative (MDAMB- 453) express high levels of Human epidermal receptor-2 (HER2), which facilitates S1PR4 stimulation to the ERK1/2 pathway.…”

“…Nonetheless, many of developed inhibitors have off-target effects with lateral effects on other lipid or protein kinases. These sphingosine analogs pointed out low robustness and selectivity such as trimethyl-sphingosine (TMS), dimethyl-sphingosine (DMS), and Safingol [ 21 ]. TMS and DMS have selectivity for both SphK2 and ceramide kinase (CERK).…”