SphK1 promotes tumor cell migration and invasion in colorectal cancer

Long, Jianting; Xie, Ying; Yin, Junmei; Lu, Wei; Shi, Fang

doi:10.1007/s13277-015-4542-4

Cited by 39 publications

(34 citation statements)

References 23 publications

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“…A cancer therapeutic directed against S1P would, ideally, shift the S1P rheostat toward reduced S1P production (1). This concept is supported by preclinical studies in multiple cancer types that demonstrate increased tumor growth when S1P is elevated either due to increased synthesis as a result of SPHK1/2 upregulation (7,8) or due to decreased S1P degradation as a result of SGPL1/2 inhibition (53). In the current study, we demonstrate that metformin reduces S1P levels by downregulating SPHK1.…”

Section: Discussionsupporting

confidence: 72%

“…Sphingosine kinases (SPHK), including SPHK1, catalyze the formation of S1P from sphingosine and are pivotal regulators of the balance between ceramides, sphingosine and S1P. Increased expression of SPHK1 promotes tumor growth and metastasis in breast, colorectal, and lung cancers (1, 3,7,8), and the role of the S1P pathway is becoming increasingly relevant in ovarian cancer (9,10). Two older studies reported higher S1P levels in the serum and ascites in ovarian cancer patients compared with controls (11,12), and a more recent study showed that SPHK1 is highly expressed in tumor stroma of high-grade serous ovarian cancer (13).…”

Section: Introductionmentioning

confidence: 99%

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SPHK1 Is a Novel Target of Metformin in Ovarian Cancer

Hart

Chiyoda

Liu

et al. 2019

Molecular Cancer Research

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The role of phospholipid signaling in ovarian cancer is poorly understood. Sphingosine-1-phosphate (S1P) is a bioactive metabolite of sphingosine that has been associated with tumor progression through enhanced cell proliferation and motility. Similarly, sphingosine kinases (SPHK), which catalyze the formation of S1P and thus regulate the sphingolipid rheostat, have been reported to promote tumor growth in a variety of cancers. The findings reported here show that exogenous S1P or overexpression of SPHK1 increased proliferation, migration, invasion, and stem-like phenotypes in ovarian cancer cell lines. Likewise, overexpression of SPHK1 markedly enhanced tumor growth in a xenograft model of ovarian cancer, which was associated with elevation of key markers of proliferation and stemness. The diabetes drug, metformin, has been shown to have anticancer effects. Here, we found that ovarian cancer patients taking metformin had significantly reduced serum S1P levels, a finding that was recapitulated when ovarian cancer cells were treated with metformin and analyzed by lipidomics. These findings suggested that in cancer the sphingolipid rheostat may be a novel metabolic target of metformin. In support of this, metformin blocked hypoxia-induced SPHK1, which was associated with inhibited nuclear translocation and transcriptional activity of hypoxiainducible factors (HIF1a and HIF2a). Further, ovarian cancer cells with high SPHK1 were found to be highly sensitive to the cytotoxic effects of metformin, whereas ovarian cancer cells with low SPHK1 were resistant. Together, the findings reported here show that hypoxia-induced SPHK1 expression and downstream S1P signaling promote ovarian cancer progression and that tumors with high expression of SPHK1 or S1P levels might have increased sensitivity to the cytotoxic effects of metformin.Implications: Metformin targets sphingolipid metabolism through inhibiting SPHK1, thereby impeding ovarian cancer cell migration, proliferation, and self-renewal.

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Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

SPHK1 Is a Novel Target of Metformin in Ovarian Cancer

Hart

Chiyoda

Liu

et al. 2019

Molecular Cancer Research

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“…SK1 expression is elevated in the majority of human CRC specimen (78-89%). 64,65 A similar increase in SK1 expression was detected in the AOM carcinogenesis model. 64 Elevated expression of SK1 also increases the susceptibility to colitis-associated cancer.…”

Section: Sphingosine Kinasessupporting

confidence: 66%

Therapeutic implications of bioactive sphingolipids: A focus on colorectal cancer

Camp

Patterson

Kester

et al. 2017

Cancer Biology & Therapy

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Therapy of colorectal cancer (CRC), especially a subset known as locally advanced rectal cancer, is challenged by progression and recurrence. Sphingolipids, a lipid subtype with vital roles in cellular function, play an important role in CRC and impact on therapeutic outcomes. In this review we discuss how dietary sphingolipids or the gut microbiome via alterations in sphingolipids influence CRC carcinogenesis. In addition, we discuss the expression of sphingolipid enzymes in the gastro-intestinal tract, their alterations in CRC, and the implications for therapy responsiveness. Lastly, we highlight some novel therapeutics that target sphingolipid signaling and have potential applications in the treatment of CRC. Understanding how sphingolipid metabolism impacts cell death susceptibility and drug resistance will be critical toward improving therapeutic outcomes.

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“…MiR-125b in bladder cancer upregulates Trop-2, SphK1, E2F3, SIRT7, MALAT1, and MMP13 to promote cancer tumorigenesis and metastasis. 67,68 In HCC, miR-125b regulates many genes involved in various mechanisms. The downregulation of miR-125b causes the overexpression of EIF5A2, which is known to be associated with proliferation and poor prognosis in patients with CRC and NSCLC.…”

Section: Downregulation Of Mir-125b In Cancermentioning

confidence: 99%

“…13,19,22,62 As tumor suppressors, miR-125b can promote the PI3K/Akt, TGFβ, and ERBB2/Her2 signaling. 67,68,72,78…”

Section: Mir-125b In Cancer Diagnosis and Prognosismentioning

confidence: 99%

<p>The Emerging Roles of miR-125b in Cancers</p>

Wang¹,

Zeng²,

Jiang³

2020

CMAR

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MicroRNAs (miRNAs) are endogenous, noncoding, single-stranded RNA molecules of 22 nucleotides in length. MiRNAs have both tumor-suppressive properties and oncogenic properties that can control critical processes in tumors. Mature miR-125b originates from miR-125b-1 and miR-125b-2 and leads to the degradation of target mRNAs or the inhibition of translation through binding to the 3′ untranslated regions (3′-UTR) of target mRNAs. Importantly, miR-125b is involved in regulating NF-κB, p53, PI3K/Akt/mTOR, ErbB2, Wnt, and another signaling pathways, thereby controlling cell proliferation, differentiation, metabolism, apoptosis, drug resistance and tumor immunity. This review aims to summarize the recent literature on the role of miR-125b in the regulation of tumorigenesis and to explore its potential clinical application in the diagnosis, prognosis and clinical treatment of tumors.

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SphK1 promotes tumor cell migration and invasion in colorectal cancer

Cited by 39 publications

References 23 publications

SPHK1 Is a Novel Target of Metformin in Ovarian Cancer

SPHK1 Is a Novel Target of Metformin in Ovarian Cancer

Therapeutic implications of bioactive sphingolipids: A focus on colorectal cancer

<p>The Emerging Roles of miR-125b in Cancers</p>

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