A Chimeric Signal Peptide-Galectin-3 Conjugate Induces Glycosylation-Dependent Cancer Cell-Specific Apoptosis.
A Chimeric Signal Peptide-Galectin-3 Conjugate Induces Glycosylation-Dependent Cancer Cell-Specific Apoptosis.
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DOI：
10.1158/1078-0432.ccr-18-3280
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发表时间：
2020-06-01
期刊：
影响因子：
--
通讯作者：
Van Meir EG
中科院分区：
文献类型：
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作者：
Lee SH;Khwaja Rehman F;Tyler KC;Yu B;Zhang Z;Osuka S;Zerrouqi A;Kaluzova M;Hadjipanayis CG;Cummings RD;Olson JJ;Devi NS;Van Meir EG
利用癌症中改变的糖基化是设计新癌症疗法的主要目标。本文设计了一种新的嵌合信号肽-半乳糖凝集素-3偶联物（sGal-3），并研究了其通过靶向异常N-糖基化的细胞表面受体诱导癌细胞死亡的能力。通过用来自组织纤溶酶原激活剂（tPA）的不可切割的信号肽延伸其N-末端，从Gal-3遗传工程化sGal-3。在体外测试sGal-3对正常细胞和肿瘤细胞的杀伤能力，并在皮下肺癌和原位恶性胶质瘤模型中评估其抗肿瘤活性。通过检测sGal-3与肿瘤细胞表面的特异性聚糖的相互作用以及引发的下游促凋亡信号传导的测定来研究杀伤机制。我们发现sGal-3优先与肿瘤细胞表面的β1整联蛋白结合，这是由于与癌症相关的几种糖基转移酶上调导致的异常N-糖基化。这种相互作用通过触发癌聚糖-β1/钙蛋白酶/半胱天冬酶-9促凋亡信号级联反应诱导有效的癌症特异性死亡。sGal-3可抑制皮下肺癌和脑中恶性胶质瘤的生长，导致动物存活率增加。我们证明sGal-3通过一种新的整合素β1依赖的细胞外源性凋亡途径杀死异常糖基化的肿瘤细胞并拮抗肿瘤生长。这些发现提供了异常N-癌聚糖代表有效癌症靶标的概念证据，并支持嵌合sGal-3肽缀合物的进一步翻译用于癌症治疗。
Exploitation of altered glycosylation in cancer is a major goal for the design of new cancer therapy. Here designed a novel chimeric signal peptide-Galectin-3 conjugate (sGal-3) and investigated its ability to induce cancer-specific cell death by targeting aberrantly N-glycosylated cell surface receptors in cancer cells. sGal-3 was genetically engineered from Gal-3 by extending its N-terminus with a non-cleavable signal peptide from tissue plasminogen activator (tPA). sGal-3 killing ability was tested on normal and tumor cells in vitro and its anti-tumor activity 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 at the surface of tumor cells and the elicited downstream pro-apoptotic signaling. We found sGal-3 preferentially binds to β1 integrin on the surface of tumor cells due to aberrant N-glycosylation resulting from cancer-associated upregulation of several glycosyltransferases. This interaction induces potent cancer-specific death by triggering an oncoglycan-β1/calpain/caspase-9 pro-apoptotic 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 concept that aberrant N-oncoglycans represent valid cancer targets and support further translation of the chimeric sGal-3 peptide conjugate for cancer therapy.