Role for sphingosine kinase 1 in colon carcinogenesis

Kawamori, Toshihiko; Kaneshiro, Tatsuya; Okumura, Masae; Maalouf, Samer; Uflacker, Andre; Bielawski, Jacek; Hannun, Yusuf A.; Obeid, Lina M.

doi:10.1096/fj.08-117572

Cited by 249 publications

(254 citation statements)

References 23 publications

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“…Accordingly, SphK1 overexpression promotes survival in response to stresses that increase ceramide content (6,8). SphK1 mRNA content was found elevated in various human (9,10) and rodent tumor tissues (11). On the contrary, SphK1 down-regulation has been associated with cell death induced by anticancer treatments (6,8,12).…”

Section: Introductionmentioning

confidence: 98%

Chemosensitizing effects of sphingosine kinase-1 inhibition in prostate cancer cell and animal models

Pchejetski

Doumerc

Golzio

et al. 2008

Molecular Cancer Therapeutics

110

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We have previously reported that, in prostate cancer, inhibition of the oncogenic sphingosine kinase-1/sphingosine 1-phosphate (SphK1/S1P) pathway is a key element in chemotherapy-induced apoptosis. Here, we show that selective pharmacologic inhibition of SphK1 triggers apoptosis in LNCaP and PC-3 prostate cancer cells, an effect that is reversed by SphK1 enforced expression. More importantly, we show for the first time that the upregulation of the SphK1/S1P pathway plays a crucial role in the resistance of prostate cancer cells to chemotherapy. Importantly, pharmacologic SphK1 inhibition with the B5354c compound sensitizes LNCaP and PC-3 cells to docetaxel and camptothecin, respectively. In vivo, camptothecin and B-5354c alone display a limited effect on tumor growth in PC-3 cells, whereas in combination there is a synergy of effect on tumor size with a significant increase in the ceramide to S1P sphingolipid ratio. To conclude, our study highlights the notion that drugs specifically designed to inhibit SphK1 could provide a means of enhancing the effects of conventional treatment through the prosurvival antiapoptotic SphK1/S1P pathway.

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Section: Introductionmentioning

confidence: 98%

Chemosensitizing effects of sphingosine kinase-1 inhibition in prostate cancer cell and animal models

Pchejetski

Doumerc

Golzio

et al. 2008

Molecular Cancer Therapeutics

110

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“…SphK1 plays a critical role in the regulation of this balance toward proliferation and survival (6). SphK1 is a tumor-associated enzyme whose expression is increased in various human (7) and mice (8) tumors. Strikingly, anti-SphK1 therapies [antiSphK1-based small interfering RNA (siRNA) or pharmacologic inhibition methods] have proven their efficacy to kill some cancer cell lines whether or not they are sensitive to conventional chemotherapy or radiotherapy, making this enzyme a very appealing candidate for anticancer therapy (7,9,10).…”

Section: Introductionmentioning

confidence: 99%

Targeting the sphingolipid metabolism to defeat pancreatic cancer cell resistance to the chemotherapeutic gemcitabine drug

Guillermet-Guibert

Davenne

Pchejetski

et al. 2009

Molecular Cancer Therapeutics

116

101

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Defeating pancreatic cancer resistance to the chemotherapeutic drug gemcitabine remains a challenge to treat this deadly cancer. Targeting the sphingolipid metabolism for improving tumor chemosensitivity has recently emerged as a promising strategy. The fine balance between intracellular levels of the prosurvival sphingosine-1-phosphate (S1P) and the proapoptotic ceramide sphingolipids determines cell fate. Among enzymes that control this metabolism, sphingosine kinase-1 (SphK1), a tumor-associated protein overexpressed in many cancers, favors survival through S1P production, and inhibitors of SphK1 are used in ongoing clinical trials to sensitize epithelial ovarian and prostate cancer cells to various chemotherapeutic drugs. We here report that the cellular ceramide/S1P ratio is a critical biosensor for predicting pancreatic cancer cell sensitivity to gemcitabine. A low level of the ceramide/S1P ratio, associated with a high SphK1 activity, correlates with a robust intrinsic pancreatic cancer cell chemoresistance toward gemcitabine. Strikingly, increasing the ceramide/S1P ratio, by using pharmacologic (SphK1 inhibitor or ceramide analogue) or small interfering RNA-based approaches to up-regulate intracellular ceramide levels or reduce SphK1 activity, sensitized pancreatic cancer cells to gemcitabine. Conversely, decreasing the ceramide/ S1P ratio, by up-regulating SphK1 activity, promoted gemcitabine resistance in these cells. Development of novel pharmacologic strategies targeting the sphingolipid metabolism might therefore represent an interesting promising approach, when combined with gemcitabine, to defeat pancreatic cancer chemoresistance to this drug.

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“…SK1 has a crucial role in determining the cellular balance of pro-apoptotic ceramide and sphingosine and pro-proliferative, pro-survival S1P, and there is now substantial evidence that SK1 has a role in tumourigenesis (Cuvillier, 2008). For example, SK1 expression is elevated in a variety of human solid tumours (French et al, 2003), overexpression of SK1 in NIH 3T3 fibroblasts leads to their neoplastic transformation , chemical inhibition or genetic ablation of SK1 reduces tumour growth in vivo (French et al, 2003;Kohno et al, 2006;Kawamori et al, 2009) and SK inhibitors or a dominant-negative SK1 can reduce neoplastic cell transformation induced by oncogenic H-Ras .…”

Section: Introductionmentioning

confidence: 99%

Guanine nucleotides regulate sphingosine kinase 1 activation by eukaryotic elongation factor 1A and provide a mechanism for eEF1A-associated oncogenesis

2010

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Sphingosine kinase 1 (SK1) catalyses the formation of bioactive phospholipid sphingosine 1-phosphate (S1P). Elevated cellular SK1 activity and S1P levels enhance cell proliferation and survival, and are strongly implicated in tumourigenesis. Regulation of SK1 activity can occur through various mechanisms, including phosphorylation and protein-protein interactions. We have previously shown that eukaryotic elongation factor 1A (eEF1A) interacts with and directly activates SK1, but the mechanisms regulating this were undefined. Notably, eEF1A has GTPase activity and can exist in GTP-or GDP-bound forms, which are associated with distinct structural conformations of the protein. Here, we show that the guanine nucleotide-bound state of eEF1A regulates its ability to activate SK1, with eEF1A.GDP, but not eEF1A.GTP, enhancing SK1 activity in vitro. Furthermore, we show that enhancing cellular eEF1A. GDP levels through expression of a guanine nucleotide dissociation inhibitor of eEF1A, translationally controlled tumour protein (TCTP), increased SK1 activity in cells. We also examined a truncated isoform of eEF1A1, termed prostate tumour inducer-1 (PTI-1), which can induce neoplastic cell transformation through undefined mechanisms. PTI-1 lacks the G protein domain of eEF1A1 and is therefore unable to undergo the GTP-binding-induced conformational change. Notably, we found that PTI-1 can directly activate SK1 and that this seems to be essential for neoplastic transformation induced by PTI-1, as chemical SK1 inhibitors or overexpression of a dominant-negative SK1 blocked this process. Thus, this study defines the mechanism regulating eEF1A-mediated SK1 activation, and also establishes SK1 as being integral for PTI-1-induced oncogenesis.

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Role for sphingosine kinase 1 in colon carcinogenesis

Cited by 249 publications

References 23 publications

Chemosensitizing effects of sphingosine kinase-1 inhibition in prostate cancer cell and animal models

Chemosensitizing effects of sphingosine kinase-1 inhibition in prostate cancer cell and animal models

Targeting the sphingolipid metabolism to defeat pancreatic cancer cell resistance to the chemotherapeutic gemcitabine drug

Guanine nucleotides regulate sphingosine kinase 1 activation by eukaryotic elongation factor 1A and provide a mechanism for eEF1A-associated oncogenesis

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