Sphingosine kinase 1 protein and mRNA are overexpressed in non-Hodgkin lymphomas and are attractive targets for novel pharmacological interventions

Abstract

Sphingosine kinase 1 (SphK1) is an oncoprotein capable of directly transforming cells and is associated with resistance to chemotherapy and radiotherapy. SphK1 is increased in various human cancers; whereas, blockade restores sensitivity to therapeutic killing in chemotherapy resistant cancer cell lines. We investigated SphK1 expression in clinical tissue samples from patients with non-Hodgkin lymphomas (NHL). Tissues from 69 patients with either NHL (n = 44) or reactive lymphoid hyperplasias (RH) (n = 25) were examined for expression of SphK1 protein by Western blot and immunohistochemistry (IHC), and SphK1 and SphK2 mRNA by quantitative real-time reverse transcriptase polymerase chain reaction. SphK1 protein (p = 0.008) and mRNA (p = 0.035) levels were higher in NHL than RH, with a clear trend toward increasing levels with increasing clinical grade (p = 0.005 for SphK1 protein, p = 0.035 for IHC score and p = 0.002 for SphK1 mRNA). IHC generally confirmed protein signal in neoplastic cells, but some lymphomas exhibited staining in non-neoplastic cells. SphK1 is overexpressed in NHL and increases with increasing clinical grade. These results, combined with prior mechanistic studies suggest that SphK1 is an attractive novel target for pharmacological interventions for NHL.

Predictive Value of Sphingosine Kinase 1 Expression in Papillary Thyroid Carcinoma

“…Sphingosine kinase 1 expression was significantly increased in thyroid cancer tissues compared to nodular goiter (p<0.001) and normal thyroid (p<0.001) tissues, consistent with previous results (14,16,20,(32)(33)(34). We observed that 34 (30.9%) of 110 papillary thyroid carcinoma tissue samples had high sphingosine kinase 1 expression.…”

Export of sphingosine-1-phosphate and cancer progression

“…In addition to cancer cells, tumors contain a repertoire of recruited ostensibly normal cells that contribute to cancer biology by creating the tumor microenvironment. Cancer cells do not manifest the disease alone, but rather conscript and corrupt resident and recruited normal cells, and collaborative ( 31 ), colon ( 34,35 ), breast ( 36,37 ), prostate ( 38 ), nonHodgkin's lymphoma ( 39 ), chronic myeloid leukemia ( 40 ), astrocytoma ( 41 ), and glioblastoma ( 42 ). In several of these studies, increased SphK1 expression correlated with increased tumor grade and poor prognosis.…”

The Apoptotic Mechanism of Action of the Sphingosine Kinase 1 Selective Inhibitor SKI-178 in Human Acute Myeloid Leukemia Cell Lines

“…Elevated expression of SphK1 is associated with numerous cancer types Sobue et al, 2008;Paugh et al, 2009;Knapp et al, 2010;Malavaud et al, 2010;Guan et al, 2011), and several lines of evidence link SphK1 deregulation with the progression of various hematologic malignancies (Van Brocklyn et al, 2005;Bonhoure et al, 2006;Bayerl et al, 2008;Paugh et al, 2008;Pitson et al, 2011). For example, overexpression of SphK1 has been shown to be an oncogenic event in acute erythroid leukemia progression (Le Scolan et al, 2005).…”