The sphingosine kinase inhibitor SKI-V suppresses cervical cancer cell growth

Overexpression and/or overactivation of sphingosine kinase 1/2 (SphK1/2) is important for tumorigenesis and progression of cervical Cancer. The current study examined the potential activity and signaling mechanisms of SKI-V, a non-lipid small molecule SphK inhibitor, against cervical Cancer cells. In different primary and immortalized cervical Cancer cells, SKI-V exerted significant anti-cancer activity by inhibiting cell viability, colony formation, proliferation, cell cycle progression and cell migration. Significant Apoptosis activation was detected in SKI-V-treated cervical Cancer cells. Significantly, SKI-V also provoked programmed necrosis cascade in cervical Cancer cells, as it induced mitochondrial p53-cyclophilin-D-adenine nucleotide translocator-1 (ANT1) complexation, mitochondrial membrane potential collapse, Reactive Oxygen Species production and the release of Lactate Dehydrogenase into the medium. Further, SKI-V blocked SphK activation and induced ceramide accumulation in primary cervical Cancer cells, without affecting SphK1/2 expression. SKI-V-induced cytotoxicity in cervical Cancer cells was largely inhibited by sphingosine-1-phosphate or the SphK1 Activator K6PC-5, but was sensitized by adding the short-chain ceramide C6. Moreover, SKI-V inhibited Akt-mTOR (mammalian target of rapamycin) activation in primary cervical Cancer cells, and its cytotoxicity was mitigated by a constitutively-active Akt. In vivo, daily intraperitoneal injection of SKI-V significantly inhibited subcutaneous primary cervical Cancer xenograft growth in nude mice. Together, the SphK inhibitor SKI-V suppresses cervical Cancer growth in vitro and in vivo.