|Year : 2017 | Volume
| Issue : 6 | Page : 209-213
Glycosylation is involved in malignant properties of cancer cells
Kazunori Hamamura1, Koichi Furukawa2
1 Department of Pharmacology, School of Dentistry, Aichi Gakuin University, Nagoya, Japan
2 Department of Life and Biomedical Sciences, Chubu University College of Life and Health Sciences, Kasugai, Japan
|Date of Web Publication||29-Dec-2017|
Dr. Kazunori Hamamura
Department of Pharmacology, School of Dentistry, Aichi Gakuin University, 1-100 Kusumoto-Cho, Chikusa-Ku, Nagoya 464-8650
Department of Life and Biomedical Sciences, Chubu University College of Life and Health Sciences, Kasugai 487-8501
Source of Support: None, Conflict of Interest: None
Cancer cells express unique carbohydrate structures in glycoproteins and glycolipids, and their structures have been considered to be cancer-associated antigens. However, the involvement of their antigens in the malignant properties has not been well understood. The functional studies of glycosyltransferase genes revealed important regulatory roles of glycosylation in the malignant properties of cancer cells. In particular, we have characterized the molecular signaling pathways that are activated or inactivated by gangliosides in various cancer cells. Our results indicated that disialyl gangliosides GD3 and GD2 enhance malignant properties of human melanoma, osteosarcoma, and small cell lung cancer cells. However, monosialyl ganglioside GM1 attenuates these properties in melanoma and lung cancer cells. In addition to glycolipids, glycoproteins are also reported to be involved in regulating malignant properties and maintenance of cancer stem cells.
Keywords: Cancer cells, glycolipids, glycoproteins, glycosylation
|How to cite this article:|
Hamamura K, Furukawa K. Glycosylation is involved in malignant properties of cancer cells. Cancer Transl Med 2017;3:209-13
| Introduction|| |
Glycosylation is biochemical process that attaches carbohydrates to proteins and lipids, and it plays crucial roles in disease onset such as inflammation, infection and degeneration, as well as homeostasis of living bodies.,,,, Many studies have revealed that glycosylation defines malignant properties of cancer cells.,, Variances of carbohydrate structures in glycoproteins and glycolipids can rewire cell signaling pathways to enhance or suppress proliferation and invasion of various cancer cells,,,, thus showing critical involvement of glycosylation in cancer progress.
The cell membrane is in the forefront to receive signals and respond to environmental changes and extrinsic stimuli. Lipid rafts in the cell membrane are key platforms for signal transduction. Localization of glycolipids in lipid rafts regulates interactions of membrane molecules to control cellular signaling.,,,,,,,
Glycosylation of proteins mainly consists of N-linked and O-linked glycans. Aberrant glycosylation of proteins is related to malignant properties of cancers and thus can be used as cancer biomarkers., For examples, our studies showed that Lewis y on the proteins in oral squamous cell carcinoma attenuates tumorigenesis, whereas the trimeric Tn antigen on syndecan-1 promotes cell adhesion and cancer metastasis., Furthermore, other studies indicate that aberrant protein glycosylation maintains stemness of cancer stem cells (CSCs).,,,, In this review, we summarize recent studies of the regulatory roles of glycosylation in cell signaling that define and maintain malignant properties of cancer cells.
| Enhancement of Malignant Properties by Disialyl Gangliosides|| |
Glycosphingolipids are classified into ganglio-, globo-, and lacto-series. Among glycosphingolipids, sialic acid-containing ganglio-series have been considered as cancer-associated carbohydrate antigens. In particular, disialyl gangliosides GD3 and GD2 are known to be highly expressed in melanomas, small cell lung cancers, and osteosarcomas.,,,, However, it was unclear how GD3 and GD2 regulate malignant properties of cancer cells. To analyze the functions of GD3 and GD2, we overexpressed glycosyltransferases cDNA and knocked down of glycosyltransferase using shRNAi in various cancer cells, respectively. Our results demonstrated that GD3 activates p130Cas, paxillin, and focal adhesion kinase (FAK) in melanoma cells, thus promoting cell proliferation and invasion [Figure 1]a., Furthermore, we showed that majority of Yes, a Src family kinase, is already localized in lipid rafts in GD3 + cells, compared to those in GD3-cells, even before any stimulation. This localization leads to the activation of Yes and the complex formation of Yes, FAK, and p130Cas. Consistently, combined siRNAs against human p130Cas and paxillin dramatically suppressed GD3-positive melanoma xenografts generated in nu/nu mice. As for adhesion signals, it was reported that GD3 recruits integrin β1 to lipid rafts to form GD3/integrin β1 clusters in lipid rafts in melanomas, leading to the enhancement of adhesion signals., Furthermore, GD3, neogenin, and γ-secretase are observed to be colocalized in lipid rafts, thus allowing efficient cleavage of neogenin by γ-secretase and conferring malignant properties of melanoma cells.,
|Figure 1: Distinct mechanisms for enhancement of malignant properties by GD3/GD2 between melanomas and osteosarcomas. (a) Mechanisms for enhancement of malignant properties by GD3 in melanomas. (b) Mechanisms for enhancement of malignant properties by GD3/GD2 in osteosarcomas|
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Most osteosarcoma cell lines have been known to express high levels of GD2; however, its functions are largely unknown. We analyzed the function of GD3/GD2 in osteosarcoma cells to found that GD3/GD2 enhanced phosphorylation of FAK, p130Cas, and paxillin, enhancing both cell migration and invasion activities [Figure 1]b. However, the mechanism of GD3/GD2 to promote cell proliferation, invasion, and migration in osteosarcomas is different from that in melanoma for two points [Figure 1]., First, Yes is colocalized with GD3 in GD3-positive melanoma cells; therefore, Yes is constitutively active. On the other hand, Lyn, instead of Yes, is activated in a GD3-dependent manner in osteosarcoma cell. Second, Lyn can directly phosphorylate paxillin, independent on FAK activation in osteosarcoma cells. However, in melanoma cells, Yes regulates phosphorylation of paxillin via FAK. These results indicate that Src family kinases are potential targets of therapeutics against GD3/GD2-positive melanomas and osteosarcomas.
In other cancers than melanomas and osteosarcoma, studies have revealed that GD3/GD2 enhances malignant properties through different mechanisms.,, For instance, it was reported that in gliomas, GD3 forms complex with platelet-derived growth factor (PDGF) receptor-α and Yes in lipid rafts to enhance PDGF/PDGF receptor signals and promote invasiveness. It has also been showed that GD2 promotes proliferation and invasion activities in both small cell lung cancer., Furthermore, GD2 has been considered to be involved in cell proliferation and cancer metastasis of breast cancer cells., The study of Cazet et al. showed that GD2 constitutively activates c-Met and promotes the growth of MDA-MB-231 breast cancer cells. Similarly, Sarkar et al. reported that GD3 synthase regulated epithelial-mesenchymal transition and metastasis in breast cancer.
| Attenuation of Malignant Properties by Monosialyl Gangliosides|| |
Different from disialyl gangliosides, it was found that monosialyl gangliosides suppress malignant properties of cancers.,,,,, We have established high metastatic sublines from mouse Lewis lung cancer, and these sublines display lower expression of monosialyl ganglioside GM1 than their parental cell lines. This result suggested a role of GM1 in reducing metastatic potentials in the lung cancers. To confirm this role, we established GM1-knockdown cells using RNAi and our results showed that GM1 dislodged integrin β1 and MMP-9 from lipid rafts to suppress MMP-9 secretion and activation. Furthermore, reduction of GM1 induces ppGalNAc-T13 expression. ppGalNAc-T13 generates trimeric Tn antigen on syndecan-1, which forms a complex with integrin a5b1 and MMP-9 to increase cell adhesion and cancer metastasis., In SK-MEL-27, a melanoma cell line, we also found that GM1 expression suppresses cell proliferation and invasion. In addition, an in vitro kinase assay of Yes in the presence of GD3 and GM1 in membranous environments showed different regulatory effects of gangliosides on Yes kinase activity. Liposome-embedded GD3 enhances the kinase activity of Yes that was isolated from GD3-negative melanoma cells, whereas liposome-embedded GM1 suppresses the kinase activity of Yes that was isolated from GD3-positive melanoma cells. In summary, these results revealed that contrast to disialyl gangliosides, monosialyl gangliosides attenuate malignant properties of cancer cells [Figure 2].
|Figure 2: Gangliosides regulate malignant properties of cancer cells by affecting localization of the molecules in lipid rafts. (a) Enhancement of malignant properties by disialyl gangliosides. (b) Attenuation of malignant properties by monosialyl gangliosides|
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| Maintenance of Cancer Stem Cells by Glycosylation|| |
Liang et al. reported the differential profiles of glycosphingolipids between human breast CSCs and cancer non-stem cells. They found that the expression levels of GD3, GD2, GM2, and GD1a were increased in human breast CSCs, and reduction of the expression levels of GD2 and GD3 caused a phenotypic change of CSC to a non-CSC. Similarly, Battula et al. reported that GD2 was identified in breast CSCs, and knockdown of GD3 synthase using shRNA reduced the CSC population and caused the abrogation of tumor formation in vivo. It was also reported that globo-series glycosphingolipids maintained the stemness of breast CSCs through activation of c-Src and b-catenin signaling.
Recent studies also demonstrated that glycoproteins as well as glycolipids are involved in modulating cancer stemness in various cancer cells.,,,, For instance, b1,4-N-acetylgalactosaminyltransferase III (B4GALNT3) activates EGFR signaling pathway to modulate cancer stemness of colon cancer cells. Furthermore, reducing expression levels of N-acetylglucosaminyltransferase V (GnT-V) altered canonical Wnt/b-catenin signaling and decreased the population of colon CSCs and attenuate their ability for self-renewal and tumorigenicity in NOD/SCID mice. In bladder cancers, GALNT1 was reported to mediate O-linked glycosylation of Sonic Hedgehog to maintain self-renewal ability of bladder CSCs. Terao et al. obtained CSC-like fractions of human pancreatic cancer cell line Panc1 from anticancer drug-resistant cells to perform lectin microarray analysis. They found that several types of fucosylation were increased in these cells and reducing fucosylation decreased anticancer drug resistance.
| Conclusion|| |
Taken together, all these studies showed that that glycosylation affects cellular signaling to regulate the malignant properties of cancer cells. Different glycosylation controls localization of signaling components in lipid rafts to regulate cell signaling transduction. Studies on glycosylation of signaling molecules will identify new therapeutic targets and develop novel strategies to manage different cancers.
Financial support and sponsorship
The study was supported in part by Grant-in-Aid for Research Activity start-up to K.H.(15H06712) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]