Signaling pathway of globo-series glycosphingolipids and β1,3-galactosyltransferase V (β3GalT5) in breast cancer

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 9; pp. 3518 - 3523
• Main Authors: Chuang, Po-Kai, Hsiao, Michael, Hsu, Tsui-Ling, Chang, Chuan-Fa, Wu, Chung-Yi, Chen, Bo-Rui, Huang, Han-Wen, Liao, Kuo-Shiang, Chen, Chen-Chun, Chen, Chi-Long, Yang, Shun-Min, Kuo, Chiung Wen, Chen, Peilin, Chiu, Ping-Tzu, Chen, I-Ju, Lai, Jiann-Shiun, Yu, Cheng-Der Tony, Wong, Chi-Huey
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 26.02.2019
• Subjects: AKT protein; Antibodies; Antigens, Tumor-Associated, Carbohydrate - genetics; Antigens, Tumor-Associated, Carbohydrate - metabolism; Apoptosis; Apoptosis - genetics; Biological Sciences; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Caveolin 1 - genetics; Caveolin 1 - metabolism; Caveolin-1; Disease Progression; FADD protein; Fas-Associated Death Domain Protein - genetics; Female; Focal adhesion kinase; Focal Adhesion Protein-Tyrosine Kinases - genetics; Galactosyltransferases - genetics; Gene Expression Regulation, Neoplastic - genetics; Glycosphingolipids; Glycosphingolipids - genetics; Glycosphingolipids - metabolism; Humans; Kinases; Lipids; Macromolecular Substances - chemistry; Macromolecular Substances - metabolism; Membrane Microdomains - genetics; Membrane Microdomains - metabolism; Metastases; Middle Aged; Protein kinase; Proteins; Proto-Oncogene Proteins c-akt - genetics; Saporins - genetics; Signal transduction; Signal Transduction - genetics; Stage-Specific Embryonic Antigens - genetics; Stage-Specific Embryonic Antigens - metabolism; Tumors; SSEA4; FAK; Globo-H; β3GalT5; SSEA3
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1816946116

The globo-series glycosphingolipids (GSLs) SSEA3, SSEA4, and Globo-H specifically expressed on cancer cells are found to correlate with tumor progression and metastasis, but the functional roles of these GSLs and the key enzyme β1,3-galactosyltransferase V (β3GalT5) that converts Gb4 to SSEA3 remain largely unclear. Here we show that the expression of β3GalT5 significantly correlates with tumor progression and poor survival in patients, and the globoseries GSLs in breast cancer cells form a complex in membrane lipid raft with caveolin-1 (CAV1) and focal adhesion kinase (FAK) which then interact with AKT and receptor-interacting protein kinase (RIP), respectively. Knockdown of β3GalT5 disrupts the complex and induces apoptosis through dissociation of RIP from the complex to interact with the Fas death domain (FADD) and trigger the Fas-dependent pathway. This finding provides a link between SSEA3/SSEA4/Globo-H and the FAK/CAV1/AKT/RIP complex in tumor progression and apoptosis and suggests a direction for the treatment of breast cancer, as demonstrated by the combined use of antibodies against Globo-H and SSEA4.