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

Abstract

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.

• Authors: Yan Zhang, Long Cheng, Xin Shi, Yu Song, Xiao-Yu Chen, Min-Bin Chen, Jin Yao, Zhi-Qing Zhang, Shang Cai
• Journal: International journal of biological sciences (Int J Biol Sci) Vol. 18 Issue 7 Pg. 2994-3005 ( 2022) ISSN: 1449-2288 [Electronic] Australia
• PMID: 35541904 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• Antineoplastic Agents
• Ceramides
• Protein Kinase Inhibitors
• Phosphotransferases (Alcohol Group Acceptor)
• sphingosine kinase
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis
• Cell Line, Tumor
• Cell Proliferation
• Ceramides (metabolism)
• Female
• Humans
• Mammals (metabolism)
• Mice
• Mice, Nude
• Phosphotransferases (Alcohol Group Acceptor) (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Uterine Cervical Neoplasms (drug therapy)