Sphingosine Kinase Isoforms Regulate Oxaliplatin Sensitivity of Human Colon Cancer Cells through Ceramide Accumulation and Akt Activation

Nemoto, Satoshi; Nakamura, Mitsuhiro; Osawa, Yohsuke; Kono, Saki; Itoh, Yoshinori; Okano, Yukio; Murate, Takashi; Hara, Akira; Ueda, Hiroshi; Nozawa, Yoshinori; Banno, Yoshiko

doi:10.1074/jbc.m900735200

Cited by 82 publications

(69 citation statements)

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“…Thus, even if the role of different sphingolipid mediators in HPR-induced cell death deserves further investigation, our data support the importance of SK in resistance to HPR. The here highlighted critical reliance on enhanced SK activity of ovarian cancer cell resistance to the chemotherapeutic HPR drug is in full agreement with previous reports in camptothecin-and docetaxelresistant prostate cancer cells (14,38), oxaliplatin-resistant colon cancer cells (15), and gemcitabine-resistant pancreatic cancer cells (17), corroborating the notion that up-regulation of SK and a concomitant decrease of the levels of sphingolipid mediators upstream of SK represent common features of resistant tumor cells.…”

Section: Discussionsupporting

confidence: 79%

“…Independently from its action mode, it is * This work was supported by the Mizutani Foundation for Glycoscience clear that ceramide and S1P exert opposite effects on cell fate, and enzymes contributing to the regulation of the relative concentrations of these lipids, such as SK, represent an essential checkpoint in determining whether a cell proliferates or undergoes apoptosis (12)(13)(14). Recently, a role of SK in the resistance of cancer cells to chemotherapy has been suggested (15)(16)(17)(18).…”

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confidence: 99%

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Sphingosine Kinase Mediates Resistance to the Synthetic Retinoid N-(4-Hydroxyphenyl)retinamide in Human Ovarian Cancer Cells

Illuzzi

Bernacchioni

Aureli

et al. 2010

Journal of Biological Chemistry

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A2780 human ovarian carcinoma cells respond to treatment with the synthetic retinoid N-(4-hydroxyphenyl)retinamide (HPR) with the production of dihydroceramide and with a concomitant reduction of cell proliferation and induction of apoptosis. The derived HPR-resistant clonal cell line, A2780/HPR, is less responsive to HPR in terms of dihydroceramide generation. In this report, we show that the production of sphingosine 1-phosphate (S1P) is significantly higher in A2780/HPR versus A2780 cells due to an increased sphingosine kinase (SK) activity and SK-1 mRNA and protein levels. Treatment of A2780 and A2780/HPR cells with a potent and highly selective pharmacological SK inhibitor effectively reduced S1P production and resulted in a marked reduction of cell proliferation. Moreover, A2780/HPR cells treated with a SK inhibitor were sensitized to the cytotoxic effect of HPR, due to an increased dihydroceramide production. On the other hand, the ectopic expression of SK-1 in A2780 cells was sufficient to induce HPR resistance in these cells. Challenge of A2780 and A2780/HPR cells with agonists and antagonists of S1P receptors had no effects on their sensitivity to the drug, suggesting that the role of SK in HPR resistance in these cells is not mediated by the S1P receptors.These data clearly demonstrate a role for SK in determining resistance to HPR in ovarian carcinoma cells, due to its effect in the regulation of intracellular ceramide/S1P ratio, which is critical in the control of cell death and proliferation.Ovarian cancer is the fifth most common cancer, and it is the leading cause of death from all types of gynecological cancer. This carcinoma has a high rate of recurrence and subsequent mortality after chemotherapy; many patients relapse after first line treatment, and only the 15% are long survivors. The failure of this kind of treatment is generally caused by the acquisition of drug resistance. Cancer cells develop multiple mechanisms to evade drug toxicity. Several commonly used anticancer drugs, including daunorubicin, vincristine, and retinoids, exert their cytotoxic action at least in part by triggering the production of the sphingolipid ceramide, a mediator of apoptosis and an inhibitor of cell proliferation in a variety of tumor cell lines (1). It has been demonstrated that chemoresistant tumor and tumor cell lines are frequently characterized by the increased glycosylation of ceramide with formation of glucosylceramide, due to an increased expression or activation of glucosylceramide synthase (2). Scavenging ceramide via its increased glycosylation would allow tumor cells to escape ceramide-induced apoptosis, thus contributing to the drug-resistant phenotype (3-5). However, it has been shown that GlcCer accumulation is not the only consequence of an altered sphingolipid metabolism in drug-resistant cancer cells. In multidrugresistant human ovarian carcinoma cells, sphingomyelin and galactosylceramide levels were also higher respect to parental sensitive cells, whereas lactosylceramide and all more compl...

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Section: Discussionsupporting

confidence: 79%

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confidence: 99%

Sphingosine Kinase Mediates Resistance to the Synthetic Retinoid N-(4-Hydroxyphenyl)retinamide in Human Ovarian Cancer Cells

Illuzzi

Bernacchioni

Aureli

et al. 2010

Journal of Biological Chemistry

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“…SphK1 was significantly elevated in azoxymethane-induced murine colon cancer tissues, SphK1 knockout mice subjected to azoxymethane had significantly less aberrant formation of crypt foci and cancer development (7). Moreover, SphK1 inhibitor or shRNA enhanced the cytotoxicity and chemosensitivity of colon cancer cells (8,9). Studies also showed that the expression of SphK1 was required for the proliferation of small intestinal tumor cell and SphK1 was able to promote intestinal adenoma progression (10).…”

Section: Introductionmentioning

confidence: 86%

Sphingosine kinase 1 promotes tumor progression and confers malignancy phenotypes of colon cancer by regulating the focal adhesion kinase pathway and adhesion molecules

Liu

Qin

et al. 2012

International Journal of Oncology

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Abstract. Studies suggest a tumor-promoting function of sphingosine kinase 1 (SphK1) in some types of human tumors, however, its effect on colon cancer is still unclear. The aims of this study were to investigate the roles of SphK1 in the progression and tumor cell phenotypic changes in colon cancer. Moreover, the focal adhesion kinase (FAK) pathway and the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were detected to explore the mechanisms of SphK1 action. In this study, the expression of SphK1, FAK and phospho-FAK (p-FAK) was analyzed in 66 surgical specimens of primary colon cancer and matched adjacent normal tissues by immunohistochemistry and western blotting. In addition, N,N-dimethylsphingosine (DMS), SphK1 DNA and shRNA transfection were used to regulate the expression and activity of SphK1 in the LOVO colon cancer cell line. Tumor cell phenotypic changes were analyzed by cell viability, invasion and apoptosis assays. Results showed that the expression of SphK1, FAK and p-FAK in colon cancer tissues were significantly stronger compared to those in matched normal tissues. There was a close correlation between the expression of SphK1 and FAK or p-FAK and the co-expression of SphK1, FAK and p-FAK significantly associated with histological grade, Dukes' stage, lymph node metastasis and distant metastasis. Overexpression of SphK1 after DNA transfection enhanced tumor cell viability and invasiveness, but suppressed cell apoptosis. In contrast, suppression of SphK1 by DMS and shRNA reduced tumor cell viability and invasiveness, but promoted cell apoptosis. The expression of FAK, p-FAK, ICAM-1 and VCAM-1 in LOVO cells were increased with the overexpression of SphK1 but decreased with the suppression of SphK1. These findings indicate that SphK1 regulates tumor cell proliferation, apoptosis and invasion, which ultimately contributes to tumor progression and malignancy phenotype in colon cancer. FAK pathway, ICAM-1 and VCAM-1 may play critical roles in this SphK1-mediated effect.

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“…GW4869 is a cell-permeable, noncompetitive, specifi c inhibitor of nSMase-2 ( 37 ), and it does not affect aSMase activity or other key TNF-mediated signaling effects, such as NF-B activation ( 38 ), GW4869 has been shown repeatedly to suppress ceramide production. For example, GW4869 signifi cantly inhibited TNF-␣ -induced ceramide production in MCF7 cells ( 38 ), signifi cantly reduced the l-OHP-induced accumulation of ceramides in human colon cancer cell line HCT116 ( 39 ), and inhibited hypoxia-induced ceramide production in rat pulmonary artery smooth muscle cells ( 20 ). Furthermore, it has been shown that anthracycline drugs, such as doxorubicin, induce ceramide production in cancer cells by activating nSMase and that inhibiting nSMase attenuates doxorubicin-induced ceramide production ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

Fatty acid synthase causes drug resistance by inhibiting TNF-α and ceramide production

Liu

Dong

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org in normal nonadipose tissues/cells. Cancer cells, however, synthesize more than 90% of their triacylglycerol de novo, requiring increased FASN expression ( 1 ). The important role of FASN in cancer cell proliferation/survival and its potential oncogenic function have been demonstrated in several previous studies ( 2-8 ).Overexpression of FASN has been associated with poor prognosis and higher risk of recurrence of human cancers of the breast ( 9-12 ) and prostate ( 13 ), as well as many other types of cancers ( 1 ), suggesting that increased FASN expression may also contribute to disease progression and treatment failure. In particular, FASN overexpression has been found in a drug-selected breast cancer cell line, and this elevation contributes to cellular resistance to Adriamycin (doxorubicin) and mitoxantrone in breast ( 14 ) and to gemcitabine in pancreatic cancer cells ( 15 ). However, the mechanism by which FASN contributes to drug resistance is currently unknown.In this study, we investigated the molecular mechanism of FASN-mediated drug resistance using FASN overexpression stable clones of MCF7 cells and found that FASN overexpression causes resistance to multiple anticancer drugs as well as to ␥ -irradiation via inhibiting treatmentinduced ceramide production, caspase 8 activation, and apoptosis. Further studies showed that FASN overexpression suppresses tumor necrosis factor (TNF)-␣ production, nuclear factor (NF)-B activation, and drug-induced activation of neutral sphingomyelinase (nSMase). Hence, FASN overexpression may cause drug resistance by inhibiting TNF-␣ expression, which in turn suppresses activation of NF-B and nSMase and, thus, reduced ceramide production, caspase 8 activation, and apoptosis.Abstract Fatty acid synthase (FASN) is a key enzyme in the synthesis of palmitate, the precursor of major nutritional, energetic, and signaling lipids. FASN expression is upregulated in many human cancers and appears to be important for cancer cell survival. Overexpression of FASN has also been found to associate with poor prognosis and higher risk of recurrence of human cancers. Indeed, elevated FASN expression has been shown to contribute to drug resistance. However, the mechanism of FASN-mediated drug resistance is currently unknown. In this study, we show that FASN overexpression causes resistance to multiple anticancer drugs via inhibiting drug-induced ceramide production, caspase 8 activation, and apoptosis. We also show that FASN overexpression suppresses tumor necrosis factor-␣ production and nuclear factor-B activation as well as drug-induced activation of neutral sphingomyelinase. Thus, TNF-␣ may play an important role in mediating FASN function in drug resistance. Mammalian FASN is a homo-dimer of a multifunctional protein of ‫ف‬ 270 kDa containing seven catalytic domains: ␤ -ketoacyl synthase, malonyl/acetyltransferase, dehydrogenase, enoyl reductase, ␤ -ketoacyl reductase, acyl carrier protein, and thioesterase . Under normal physiologi...

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Sphingosine Kinase Isoforms Regulate Oxaliplatin Sensitivity of Human Colon Cancer Cells through Ceramide Accumulation and Akt Activation

Cited by 82 publications

References 47 publications

Sphingosine Kinase Mediates Resistance to the Synthetic Retinoid N-(4-Hydroxyphenyl)retinamide in Human Ovarian Cancer Cells

Sphingosine Kinase Mediates Resistance to the Synthetic Retinoid N-(4-Hydroxyphenyl)retinamide in Human Ovarian Cancer Cells

Sphingosine kinase 1 promotes tumor progression and confers malignancy phenotypes of colon cancer by regulating the focal adhesion kinase pathway and adhesion molecules

Fatty acid synthase causes drug resistance by inhibiting TNF-α and ceramide production

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