A Chimeric Signal Peptide-Galectin-3 Conjugate Induces Glycosylation-Dependent Cancer Cell-Specific Apoptosis

• Published in: Clinical cancer research 2020-06, Vol.26 (11), p.2711-2724
• Main Authors: Lee, Sok-Hyong, Khwaja Rehman, Fatima, Tyler, Kari C, Yu, Bing, Zhang, Zhaobin, Osuka, Satoru, Zerrouqi, Abdessamad, Kaluzova, Milota, Hadjipanayis, Costas G, Cummings, Richard D, Olson, Jeffrey J, Devi, Narra S, Van Meir, Erwin G
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Blood Proteins - genetics; Blood Proteins - metabolism; Cell Proliferation; Female; Galectins - genetics; Galectins - metabolism; Glioma - drug therapy; Glioma - metabolism; Glioma - pathology; Glycosylation; Humans; Integrin beta1 - genetics; Integrin beta1 - metabolism; Mice; Mice, Nude; Peptide Fragments - pharmacology; Protein Sorting Signals; Signal Transduction; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-3280

Exploitation of altered glycosylation in cancer is a major goal for the design of new cancer therapy. Here, we designed a novel secreted chimeric signal peptide-Galectin-3 conjugate (sGal-3) and investigated its ability to induce cancer-specific cell death by targeting aberrantly glycosylated cell surface receptors on cancer cells. sGal-3 was genetically engineered from Gal-3 by extending its N-terminus with a noncleavable signal peptide from tissue plasminogen activator. sGal-3 killing ability was tested on normal and tumor cells and its antitumor activity was evaluated in subcutaneous lung cancer and orthotopic malignant glioma models. The mechanism of killing was investigated through assays detecting sGal-3 interaction with specific glycans on the surface of tumor cells and the elicited downstream proapoptotic signaling. We found sGal-3 preferentially binds to β1 integrin on the surface of tumor cells due to aberrant -glycosylation resulting from cancer-associated upregulation of several glycosyltransferases. This interaction induces potent cancer-specific death by triggering an oncoglycan-β1/calpain/caspase-9 proapoptotic signaling cascade. sGal-3 could reduce the growth of subcutaneous lung cancers and malignant gliomas in brain, leading to increased animal survival. We demonstrate that sGal-3 kills aberrantly glycosylated tumor cells and antagonizes tumor growth through a novel integrin β1-dependent cell-extrinsic apoptotic pathway. These findings provide proof-of-principle that aberrant -oncoglycans represent valid cancer targets and support further translation of the chimeric sGal-3 peptide conjugate for cancer therapy.