Purpose: 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 N- glycosylated cell surface receptors on cancer cells. Experimental Design: 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 in vitro 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. Results: 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 proapoptotic signaling cascade. sGal-3 could reduce the growth of subcutaneous lung cancers and malignant gliomas in brain, leading to increased animal survival. Conclusions: 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 N -oncoglycans represent valid cancer targets and support further translation of the chimeric sGal-3 peptide conjugate for cancer therapy.

中文翻译：

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嵌合信号肽-Galectin-3 缀合物诱导糖基化依赖性癌细胞特异性细胞凋亡。

目的：利用癌症中改变的糖基化是设计新癌症疗法的主要目标。在这里，我们设计了一种新型分泌型嵌合信号肽-Galectin-3缀合物（sGal-3），并研究了其通过靶向癌细胞上异常N-糖基化的细胞表面受体来诱导癌症特异性细胞死亡的能力。实验设计：sGal-3 是从 Gal-3 基因改造而来，通过用来自组织纤溶酶原激活剂的不可切割信号肽延伸其 N 末端。在体外测试了 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了其抗肿瘤活性。通过检测 sGal-3 与肿瘤细胞表面特定聚糖的相互作用以及引发的下游促凋亡信号传导来研究杀伤机制。结果：我们发现 sGal-3 优先与肿瘤细胞表面的 β1 整合素结合，这是由于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/Caspase-9 促凋亡信号级联，诱导有效的癌症特异性死亡。sGal-3 可以减少皮下肺癌和脑部恶性胶质瘤的生长，从而提高动物的存活率。结论：我们证明 sGal-3 通过一种新的整合素 β1 依赖性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。这些发现提供了原理证明，即异常的 N -癌聚糖代表有效的癌症靶标，并支持嵌合 sGal-3 肽缀合物用于癌症治疗的进一步转化。