Targeting SphK1/2 by SKI-178 inhibits prostate cancer cell growth

Abstract

Sphingosine kinases (SphK), including SphK1 and SphK2, are important enzymes promoting progression of prostate cancer. SKI-178 is a novel and highly potent SphK1/2 dual inhibitor. We here tested the potential anti-prostate cancer cell activity of SKI-178. Bioinformatics analyses and results from local tissues demonstrated that that both SphK1 and SphK2 are upregulated in human prostate cancer tissues. Ectopic overexpression of SphK1 and SphK2, by lentiviral constructs, promoted primary prostate cancer cell proliferation and migration. In primary human prostate cancer cells and immortalized cell lines, SKI-178 potently inhibited cell viability, proliferation, cell cycle progression and cell migration, causing robust cell death and apoptosis. SKI-178 impaired mitochondrial functions, causing mitochondrial depolarization, reactive oxygen species production and ATP depletion.SKI-178 potently inhibited SphK activity and induced ceramide production, without affecting SphK1/2 expression in prostate cancer cells. Further, SKI-178 inhibited Akt-mTOR activation and induced JNK activation in prostate cancer cells. Contrarily, a constitutively-active Akt1 construct or the pharmacological JNK inhibitors attenuated SKI-178-induced cytotoxicity in prostate cancer cells. In vivo, daily intraperitoneal injection of a single dose of SKI-178 potently inhibited PC-3 xenograft growth in nude mice. SphK inhibition, ceramide production, ATP depletion and lipid peroxidation as well as Akt-mTOR inactivation and JNK activation were detected in PC-3 xenograft tissues with SKI-178 administration. Together, targeting SphK1/2 by SKI-178 potently inhibited prostate cancer cell growth in vitro and in vivo.

SPHK1 promotes the migration and invasion of gastric cancer cells through NF-κB pathway

“…The migration and invasion of tumor cells are the key links in the metastasis process [27]. SPHK1 has demonstrated tumor cell migration and invasion functions in breast cancer [28] and prostate cancer [29]. Consistent with the above ndings, our data showed that SPHK1 knockdown inhibited GC cell migration and invasion, while overexpression of SPHK1 did the opposite (Fig.…”

The Role of Sphingolipids and Sphingosine-1-phosphate—Sphingosine-1-phosphate-receptor Signaling in Psoriasis

“…Hence, ceramide generation via de novo synthesis and sphingomyelin hydrolysis aids in treating cancer. On the other hand, the suppression of enzymes that deplete ceramide-for instance, ceramidases, glucosylceramide synthase, or SphKs-when combined with standard cancer therapies that dysregulate these enzymes, reveal promising improvements in the patient response to various cancer therapies [38][39][40].…”