sphingosine-kinase and Carcinogenesis

Sphingosine kinases (Sphk1 and 2) regulate the prodution of sphingosine-1-phosphate (S1P), that is key molecule in cancer development. SphK1, which is commonly overexpressed in malignant tumours, significantly contributes to the pathogenesis of various types of cancer as well as to resistance to different Tyrosine Kinase inibitors (TKIs). Even, SphK2 may promote apoptosis and inhibit cell growth but its role has not yet been fully understood in pathologic conditions. Different growth factorsinduced activation of receptor tyrosine kinases (RTKs) results in production of Sphk1 which catalyzes the phosphorylation of sphingosine. Such enzyme, in turn, is involved in many cellular processes by its five receptors. These are able to transactivate RTKs through amplification of a positive-feedback signaling loop. In conclusion, development of pharmacological inhibitors of SphK1 has been limited by the lack of completely understanding of the enzymatic activation mechanisms of SphK1.

Topics: Animals; Carcinogenesis; Drug Resistance, Neoplasm; Humans; Neoplasms; Phosphotransferases (Alcohol Group Acceptor); Signal Transduction; Sphingolipids

Sphingosine-1-phosphate (S1P) signaling has been widely explored as a therapeutic target in cancer. Sphingosine kinase 2 (SK2), one of the kinases that phosphorylate sphingosine, has a cell type and cell location-dependent mechanism of action, so the ability of SK2 to induce cell cycle arrest, apoptosis, proliferation, and survival is strongly influenced by the cell-context. In contrast to SK1, which is widely studied in different types of cancer, including head and neck cancer, the role of SK2 in the development and progression of oral cancer is still poorly understood. In order to elucidate SK2 role in oral cancer, we performed the overexpression of SK2 in non-tumor oral keratinocyte cell (NOK SK2) and in oral squamous cell carcinoma (HN12 SK2), and RNA interference for SK2 in another oral squamous cell carcinoma (HN13 shSK2). In our study we demonstrate for the first time that accumulation of SK2 can be a starting point for oncogenesis and transforms a non-tumor oral keratinocyte (NOK-SI) into highly aggressive tumor cells, even acting on cell plasticity. Furthermore, in oral metastatic cell line (HN12), SK2 contributed even more to the tumorigenesis, inducing proliferation and tumor growth. Our work reveals the intriguing role of SK2 as an oral tumor promoter and regulator of different pathways and cellular processes.

Topics: Autophagy; Carcinogenesis; Carcinoma, Squamous Cell; Cell Proliferation; Cell Transformation, Neoplastic; Head and Neck Neoplasms; Humans; Keratinocytes; Mouth Neoplasms; Squamous Cell Carcinoma of Head and Neck

Aberrant gene expression plays critical roles in the development of colorectal cancer (CRC). Here we show that POTEE, which was identified as a member E of POTE ankyrin domain family, was significantly upregulated in colorectal tumors and predicted poor overall survival of CRC patients. In CRC cells, POTEE could act as an oncogene and could promote cell growth, cell-cycle progression, inhibit apoptosis, and elevates xenograft tumor growth. Mechanically, we used microarray analysis and identified a POTEE/SPHK1/p65 signaling axis, which affected the biological functions of CRC cells. Further evaluation showed that overexpression of POTEE could increase the protein expression of SPHK1, followed by promoting the phosphorylation and activation of p65 protein. Altogether, our findings suggested a POTEE/SPHK1/p65 signaling axis could promote colorectal tumorigenesis and POTEE might potentially serve as a novel biomarker for the diagnosis and an intervention of colorectal cancer.

Topics: Aged; Antigens, Neoplasm; Carcinogenesis; Cell Line, Tumor; Cell Movement; Colorectal Neoplasms; Disease-Free Survival; eIF-2 Kinase; Female; Gene Expression Regulation, Neoplastic; Humans; Lymphatic Metastasis; Male; Middle Aged; Phosphotransferases (Alcohol Group Acceptor); Signal Transduction

While the two mammalian sphingosine kinases, SK1 and SK2, both catalyze the generation of pro-survival sphingosine 1-phosphate (S1P), their roles vary dependent on their different subcellular localization. SK1 is generally found in the cytoplasm or at the plasma membrane where it can promote cell proliferation and survival. SK2 can be present at the plasma membrane where it appears to have a similar function to SK1, but can also be localized to the nucleus, endoplasmic reticulum or mitochondria where it mediates cell death. Although SK2 has been implicated in cancer initiation and progression, the mechanisms regulating SK2 subcellular localization are undefined. Here, we report that SK2 interacts with the intermediate chain subunits of the retrograde-directed transport motor complex, cytoplasmic dynein 1 (DYNC1I1 and -2), and we show that this interaction, particularly with DYNC1I1, facilitates the transport of SK2 away from the plasma membrane. DYNC1I1 is dramatically downregulated in patient samples of glioblastoma (GBM), where lower expression of DYNC1I1 correlates with poorer patient survival. Notably, low DYNC1I1 expression in GBM cells coincided with more SK2 localized to the plasma membrane, where it has been recently implicated in oncogenesis. Re-expression of DYNC1I1 reduced plasma membrane-localized SK2 and extracellular S1P formation, and decreased GBM tumor growth and tumor-associated angiogenesis in vivo. Consistent with this, chemical inhibition of SK2 reduced the viability of patient-derived GBM cells in vitro and decreased GBM tumor growth in vivo. Thus, these findings demonstrate a tumor-suppressive function of DYNC1I1, and uncover new mechanistic insights into SK2 regulation which may have implications in targeting this enzyme as a therapeutic strategy in GBM.

Topics: Animals; Apoptosis; Carcinogenesis; Cell Line, Tumor; Cell Membrane; Cell Proliferation; Cytoplasmic Dyneins; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Glioblastoma; HEK293 Cells; Humans; Lysophospholipids; Mice; Phosphotransferases (Alcohol Group Acceptor); Sphingosine; Xenograft Model Antitumor Assays

Topics: Adamantane; Animals; Apoptosis; Carcinogenesis; Cell Proliferation; Cell Survival; DNA Repair; Hematologic Neoplasms; Humans; Hydrazines; Mast Cells; Mastocytosis; Mice; Mice, Knockout; Mutation; Phosphotransferases (Alcohol Group Acceptor); Protein Isoforms; Proto-Oncogene Proteins c-kit; Pyrazoles; Pyridines; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Accumulating evidence suggests that sphingosine kinase 1 (SphK1)/sphingosine 1-phosphate pathway plays a pivotal role in colon carcinogenesis.. To further support the evidence, we investigated the effects of SphK1 using three separate animal models: SphK1 knockout mice, SphK1 overexpressing transgenic mice, and SphK1 overexpression in human colon cancer xenografts. Using azoxymethane (AOM, colon carcinogen), we analyzed colon tumor development in SphK1 KO and SphK1 overexpression in intestinal epithelial cells regulated by a tet-on system. Then, we analyzed subcutaneous tumor growth using xenografts of HT-29 human colon cancer cell. Finally, immunohistochemical analyses for SphK1 and COX-2 were performed on human colon cancer tissue microarray.. SphK1 KO mice, compared to wild-type mice, demonstrated a significant inhibition in colon cancer development induced by AOM (58.6% vs. 96.4%, respectively, P < 0.005). Tumor multiplicity (1.00 vs. 1.64 per colon, respectively, P < 0.05) and tumor volume (14.82 mm. SphK1 expression regulates the early stage of colon carcinogenesis and tumor growth, thus inhibition of SphK1 may be an effective strategy for colon cancer chemoprevention.

Topics: Aged; Animals; Azoxymethane; Carcinogenesis; Cell Proliferation; Colonic Neoplasms; Cyclooxygenase 2; Enterocytes; Female; HT29 Cells; Humans; Male; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Neoplasm Staging; Phosphotransferases (Alcohol Group Acceptor)

Accumulating evidence suggests that the sphingosine kinase 1 (SphK1)/sphingosine 1-phosphate (S1P) pathway plays a pivotal role in colon carcinogenesis. Our previous studies indicate that the SphK1/S1P pathway mediates colon carcinogenesis at least by regulating cyclooxygenase 2 (COX-2) expression and prostaglandin E2 (PGE2) production. However, the mechanisms by which this pathway regulates colon carcinogenesis are still unclear. First, we show that SphK1 deficient mice significantly attenuated azoxymethane (AOM)-induced colon carcinogenesis as measured by colon tumor incidence, multiplicity, and volume. We found that AOM activates peritoneal macrophages to induce SphK1, COX-2, and tumor necrosis factor (TNF)-α expression in WT mice. Interestingly, SphK1 knockout (KO) mice revealed significant reduction of COX-2 and TNF-α expression from AOM-activated peritoneal macrophages, suggesting that SphK1 regulates COX-2 and TNF-α expression in peritoneal macrophages. We found that inoculation of WT peritoneal macrophages restored the carcinogenic effect of AOM in Sphk1 KO mice as measured by aberrant crypt foci (ACF) formation, preneoplastic lesions of colon cancer. In addition, downregulation of SphK1 only in peritoneal macrophage by short hairpin RNA (shRNA) reduced the number of ACF per colon induced by AOM. Intraperitoneal injection of sphingolipids demonstrates that S1P enhanced AOM-induced ACF formation, while ceramide inhibited. Finally, we show that SphK inhibitor SKI-II significantly reduced the number of ACF per colon. These results suggest that SphK1 expression plays a pivotal role in the early stages of colon carcinogenesis through regulating COX-2 and TNF-α expression from activated peritoneal macrophages.

Topics: Animals; Carcinogenesis; Colonic Neoplasms; Macrophages, Peritoneal; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphotransferases (Alcohol Group Acceptor)

CIB1 (calcium and integrin binding protein 1) is a small intracellular protein with numerous interacting partners, and hence has been implicated in various cellular functions. Recent studies have revealed emerging roles of CIB1 in regulating cancer cell survival and angiogenesis, although the mechanisms involved have remained largely undefined. In investigating the oncogenic function of CIB1, we initially found that CIB1 is widely up-regulated across a diverse range of cancers, with this upregulation frequently correlating with oncogenic mutations of KRas. Consistent with this, we found that ectopic expression of oncogenic KRas and HRas in cells resulted in elevated CIB1 expression. We previously described the Ca

Topics: Calcium; Calcium-Binding Proteins; Carcinogenesis; Cell Line, Tumor; Cell Membrane; Cell Survival; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Phosphotransferases (Alcohol Group Acceptor); Proto-Oncogene Proteins p21(ras)