When the Sphingosine Kinase 1/Sphingosine 1-Phosphate Pathway Meets Hypoxia Signaling: New Targets for Cancer Therapy

Ader, Isabelle; Malavaud, Bernard; Cuvillier, Olivier

doi:10.1158/0008-5472.can-09-0389

Cited by 68 publications

(58 citation statements)

References 33 publications

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“…45 Interestingly, SK1 was recently shown to enhance hypoxiainducible factor-1a stability and function. 46,47 Notably, this is consistent with another study that demonstrated that S1P increases hypoxia-inducible factor-1a protein stability through activation of the S1P 2 receptor, 48 suggesting that SK1/S1P may increase TFR1 transcription through the accumulation of hypoxiainducible factor-1a. Clearly, further studies are required to investigate these possibilities.…”

Section: Discussionsupporting

confidence: 89%

Enhanced expression of transferrin receptor 1 contributes to oncogenic signalling by sphingosine kinase 1

et al. 2013

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Sphingosine kinase 1 (SK1) is a lipid kinase that catalyses the formation of sphingosine-1-phosphate (S1P). Considerable evidence has implicated elevated cellular SK1 in tumour development, progression and disease severity. In particular, SK1 has been shown to enhance cell survival and proliferation and induce neoplastic transformation. Although S1P has been found to have both cell-surface G-protein-coupled receptors and intracellular targets, the specific downstream pathways mediating oncogenic signalling by SK1 remain poorly defined. Here, using a gene expression array approach, we have demonstrated a novel mechanism whereby SK1 regulates cell survival, proliferation and neoplastic transformation through enhancing expression of transferrin receptor 1 (TFR1). We showed that elevated levels of SK1 enhanced total as well as cell-surface TFR1 expression, resulting in increased transferrin uptake into cells. Notably, we also found that SK1 activation and localization to the plasma membrane, which are critical for its oncogenic effects, are necessary for regulation of TFR1 expression specifically through engagement of the S1P G-protein coupled receptor, S1P2. Furthermore, we showed that blocking TFR1 function with a neutralizing antibody inhibits SK1-induced cell proliferation, survival and neoplastic transformation of NIH3T3 fibroblasts. Similar effects were observed following antagonism of S1P2. Together these findings suggest that TFR1 has an important role in SK1-mediated oncogenesis.

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Section: Discussionsupporting

confidence: 89%

Enhanced expression of transferrin receptor 1 contributes to oncogenic signalling by sphingosine kinase 1

et al. 2013

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“…To explore the mechanisms underlying the resistence effects of SphK1, we tested the effect of SphK1 on the AKT/GSK3β pathways, which have been demonstrated to be involved in tumor progression (24). We have demonstrated in the present study that p-Akt and p-GSK3β was downregulated in SphK1-knocked down HCC cells, suggested Akt/GSK3β activation through SphK1 signaling is associated with oxaliplatin resistance in HCC cells.…”

Section: Discussionmentioning

confidence: 52%

“…Overexpression of SphK1 may confer the development of resistance to chemotherapeutics, whereas disruption of SphK1/S1P signaling may restore or improve chemotherapy sensitivity (24). For example, raised SphK1 has been associated with chronic myeloid leukemia resistance to imatinib and pancreatic cancer cell resistance to gemcitabine (16,25).…”

Section: Discussionmentioning

confidence: 99%

Sphingosine kinase 1 overexpression is associated with poor prognosis and oxaliplatin resistance in hepatocellular carcinoma

Wang¹,

2018

Exp Ther Med

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Abstract. Sphingosine kinase 1 (SphK1) is a tumor-associated protein overexpressed in numerous types of cancer and is involved in the regulation of resistance to multiple chemotherapeutic agents. However, the role of SphK1 in the resistance of hepatocellular carcinoma (HCC) to oxaliplatin remains unclear. In the present study, the transcriptional levels of SphK1 were analyzed in 21 patients with HCC and the SphK1 expression levels were identified to be significantly upregulated in HCC tissue compared with that in adjacent normal tissue samples (P<0.001). High SphK1 expression correlated with shorter overall survival times in patients with HCC (P<0.05). Furthermore, SphK1 expression levels and activity were analyzed in a series of HCC cell lines and they were both demonstrated to be associated with resistance to oxaliplatin. Conversely, the knockdown of SphK1 protein expression resulted in decreased oxaliplatin resistance in SK-Hep1 and HCCLM3 cell lines. In addition, the results of the current study demonstrated that the downregulation of SphK1 decreased the levels of phosphorylated AKT serine/threonine kinase (Akt) and glycogen synthase kinase-3β (GSK3β), suggesting that SphK1 promotes oxaliplatin resistance of HCC cells via modulation of the Akt/GSK3β signaling pathway. To the best of our knowledge, the present study is the first to report that SphK1 is associated with poor prognosis and oxaliplatin resistance in HCC. Thus, the findings of the current study have provided a direction for the identification of novel therapeutic targets for the treatment of HCC.

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“…Although both subtypes catalyze the same reaction, it remains unclear whether they have overlapping or diverging cellular functions [5]. Accumulating evidence now suggests a key role for SK-1 in cell proliferation and migration implicating a role of this subtype in tumour growth and metastasis formation [4][5][6][7]. Additionally, the overexpression of SK-1 in mouse fibroblasts leads to foci formation in soft agar thus, suggesting that the SPHK1 gene may act as an oncogene [8].…”

Section: Introductionmentioning

confidence: 99%

A Novel Mode of Action of the Putative Sphingosine Kinase Inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophenyl) Thiazole (SKI II): Induction of Lysosomal Sphingosine Kinase 1 Degradation

Ren

Xin

Pfeilschifter

et al. 2010

Cell Physiol Biochem

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Background: Sphingosine kinase 1 (SK1) is a key enzyme in the generation of sphingosine 1-phosphate (S1P) which critically regulates a variety of important cell responses such as proliferation and migration. Therefore, inhibition of SK-1 has been suggested to be an attractive approach to treat tumor growth and metastasis formation. Results: We show here that the previously developed putative SK-1 inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole (SKI II) displays an additional facet of action complementary to the known inhibition of enzymatic SK-1 activity. In various human cell lines including glomerular podocytes and mesangial cells, the human endothelial cell line EA.hy 926, and the lung cancer cell line NCI H358, SKI II reduced TGFΒ- and TPA-stimulated cellular SK-1 activity by downregulating SK-1 protein expression without affecting SK-1 mRNA expression. By using cycloheximide to block the de novo protein synthesis, the protein expression of SK-1 under untreated conditions was stable over 24h. Under SKI II treatment, the half-live drastically decreased to approximately 0.8h. Mechanistically, this degradation occurred through a lysosomal pathway and involved cathepsin B since the general lysosomal inhibitor chloroquine and the specific cathepsin B inhibitor CA-074ME were able to reverse the effect of SKI II. Surprisingly, in vitro SK-1 activity assays revealed only a very weak direct inhibitory effect of SKI II on SK-1 overexpressed HEK293 cell lysates. Conclusion: These data show for the first time that the previously developed SK inhibitor SKI II hardly inhibits SK-1 directly but rather acts by triggering the lysosomal degradation of SK-1 in various cell types. This finding discloses a new mode of action of SKI II and strongly suggests that additional direct targets of SKI II may exist other than SK-1.

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When the Sphingosine Kinase 1/Sphingosine 1-Phosphate Pathway Meets Hypoxia Signaling: New Targets for Cancer Therapy

Cited by 68 publications

References 33 publications

Enhanced expression of transferrin receptor 1 contributes to oncogenic signalling by sphingosine kinase 1

Enhanced expression of transferrin receptor 1 contributes to oncogenic signalling by sphingosine kinase 1

Sphingosine kinase 1 overexpression is associated with poor prognosis and oxaliplatin resistance in hepatocellular carcinoma

A Novel Mode of Action of the Putative Sphingosine Kinase Inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophenyl) Thiazole (SKI II): Induction of Lysosomal Sphingosine Kinase 1 Degradation

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