title: Sphingosine kinase 1 promotes malignant progression in colon cancer and independently predicts survival of patients with colon cancer by competing risk approach in South asian population.
abstract: OBJECTIVE
  Sphingosine kinase 1 (SphK1) phosphorylates the membrane sphingolipid, sphingosine, to sphingosine-1-phosphate (S1P), an oncogenic mediator, which drives tumor cell growth and survival. Although SphK1 has gained increasing prominence as an oncogenic determinant in several cancers, its potential as a therapeutic target in colon cancer remains uncertain. We investigated the clinical relevance of SphK1 expression in colon cancer as well as its inhibitory effects in vitro.
  
  
  METHODS
  SphK1 expression in human colon tumor tissues was determined by immunohistochemistry and its clinicopathological significance was ascertained in 303 colon cancer cases. The effects of SphK1 inhibition on colon cancer cell viability and the phosphoinositide 3-kinase (PI3K)/Akt cell survival pathway were investigated using a SphK1-selective inhibitor-compound 5c (5c). The cytotoxicity of a novel combination using SphK1 inhibition with the chemotherapeutic drug, 5-fluorouracil (5-FU), was also determined.
  
  
  RESULTS
  High SphK1 expression correlated with advanced tumor stages (AJCC classification). Using a competing risk analysis model to take into account disease recurrence, we found that SphK1 is a significant independent predictor for mortality in colon cancer patients. In vitro, the inhibition of SphK1 induced cell death in colon cancer cell lines and attenuated the serum-dependent PI3K/Akt signaling. Inhibition of SphK1 also enhanced the sensitivity of colon cancer cells to 5-FU.
  
  
  CONCLUSIONS
  Our findings highlight the impact of SphK1 in colon cancer progression and patient survival, and provide evidence supportive of further development in combination strategies that incorporate SphK1 inhibition with current chemotherapeutic agents to improve colon cancer outcomes.
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Sheryl S L
authors.initials: SS
authors.lastname: Tan
authors.affiliation: 1] Investigational Medicine Unit, Dean's Office, Yong Loo Lin School of Medicine, National University of Singapore, Singapore [2] Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Lay W
authors.initials: LW
authors.lastname: Khin
authors.affiliation: Department of Chemistry, Faculty of Science, National University of Singapore, Singapore, Singapore.
authors.forename: Lingkai
authors.initials: L
authors.lastname: Wong
authors.affiliation: 1] Department of Pathology, National University Health System and National University of Singapore, Singapore [2] Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore.
authors.forename: Benedict
authors.initials: B
authors.lastname: Yan
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Chee W
authors.initials: CW
authors.lastname: Ong
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Arpita
authors.initials: A
authors.lastname: Datta
authors.affiliation: 1] Department of Pathology, National University Health System and National University of Singapore, Singapore [2] Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Manuel
authors.initials: M
authors.lastname: Salto-Tellez
authors.affiliation: Department of Chemistry, Faculty of Science, National University of Singapore, Singapore, Singapore.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Lam
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Celestial T
authors.initials: CT
authors.lastname: Yap