Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, 91-95 Blvd. Splaiul Independentei, 050095, Bucharest, Romania.
Department of Preclinic Sciences, Faculty of Veterinary Medicine, University of Agronomic Sciences and Veterinary Medicine of Bucharest, 105 Blvd. Splaiul Independentei, 050097, Bucharest, Romania.
Sci Rep. 2020 Feb 17;10(1):2754. doi: 10.1038/s41598-020-59623-x.
The number of colon cancer cases is increasing worldwide, and type II diabetes patients have an increased risk of developing colon cancer. Diet-borne advanced glycation end-products (AGEs) may promote neoplastic transformation; however, the mechanisms involved remain elusive. The present study helped to define the relationship between dietary AGEs and cancer progression. C2BBe1 adenocarcinoma enterocytes were exposed to 200 µg/mL glycated casein (AGEs-Csn) for up to 24 h. AGEs-Csn exposure resulted in increased cell proliferation, maladaptative changes in SOD and CAT activity and moderate levels of hydrogen peroxide (HO) intracellular accumulation. AGEs-Csn activated pro-survival and proliferation signalling, such as the phosphorylation of mTOR (Ser2448) and Akt (Ser473). GSK-3β phosphorylation also increased, potentially inducing extracellular matrix remodelling and thus enabling metastasis. Moreover, AGEs-Csn induced MMP-1, -3, -7, -9 and -10 expression and activated MMP-2 and MMP-9, which are regulators of the extracellular matrix and cytokine functions. AGEs-Csn induced inflammatory responses that included extracellular IL-1β at 6 h; time-dependent increases in IL-8; RAGE and NF-κB p65 upregulation; and IκB inhibition. Co-treatment with anti-RAGE or anti-TNF-α blocking antibodies and AGEs-Csn partially counteracted these changes; however, IL-8, MMP-1 and -10 expression and MMP-9 activation were difficult to prevent. AGEs-Csn perpetuated signalling that led to cell proliferation and matrix remodelling, strengthening the link between AGEs and colorectal cancer aggressiveness.
全世界结肠癌的发病率正在上升，而 2 型糖尿病患者患结肠癌的风险增加。饮食来源的晚期糖基化终产物（AGEs）可能促进肿瘤转化；然而，相关的机制仍不清楚。本研究有助于定义饮食 AGEs 与癌症进展之间的关系。C2BBe1 腺癌细胞暴露于 200μg/ml 糖化酪蛋白（AGEs-Csn）中，最长达 24 小时。AGEs-Csn 暴露导致细胞增殖增加、SOD 和 CAT 活性适应性变化以及中等水平的过氧化氢（HO）细胞内积累。AGEs-Csn 激活了促生存和增殖信号，如 mTOR（Ser2448）和 Akt（Ser473）的磷酸化。GSK-3β 的磷酸化也增加，可能诱导细胞外基质重塑，从而促进转移。此外，AGEs-Csn 诱导 MMP-1、-3、-7、-9 和 -10 的表达，并激活 MMP-2 和 MMP-9，它们是细胞外基质和细胞因子功能的调节剂。AGEs-Csn 诱导的炎症反应包括 6 小时时细胞外的 IL-1β；IL-8 的时间依赖性增加；RAGE 和 NF-κB p65 的上调；以及 IκB 的抑制。用抗 RAGE 或抗 TNF-α 阻断抗体与 AGEs-Csn 共同处理部分抵消了这些变化；然而，IL-8、MMP-1 和 -10 的表达和 MMP-9 的激活很难预防。AGEs-Csn 延续了导致细胞增殖和基质重塑的信号，加强了 AGEs 与结直肠癌侵袭性之间的联系。
