Division of Endocrinology, Diabetes, and Metabolism, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, JP9B52A, 150 South Huntington Avenue, Boston, Massachusetts 02130, USA.
Endocr Relat Cancer. 2013 Oct 24;20(6):849-59. doi: 10.1530/ERC-13-0240. Print 2013 Dec.
Both adiponectin (AD) and metformin (Met) have been proposed to downregulate cell proliferation of colon cancer cells, but whether their effect might be additive has not been studied to date. Genetic studies in humans have suggested an important role for interleukin 1β (IL1β) in cancer pathogenesis. Direct evidence that IL1β contributes to the development of colon cancer has not yet been fully confirmed and no previous studies have evaluated how IL1β may interact with AD and/or Met to regulate malignant potential and intracellular signaling pathways in human and mouse colon cancer cells. We conducted in vitro studies using human (LoVo) and mouse (MCA38) colon cancer cell lines to evaluate whether AD and Met alone or in combination may antagonize IL1β-regulated malignant potential in human and mouse colon cancer cell lines. IL1β increased malignant potential and regulated the expression of tumor suppressor (p53) and cell cycle regulatory genes (p21, p27, and cyclin E2) in human and mouse colon cancer cell lines. These effects were reversed by co-administration of AD and/or Met and were additively altered by AD and Met in combination in a STAT3- and AMPK/LKB1-dependent manner. We also observed using fluorescence activated cell sorter analysis that IL1β-regulated cell cycle progression is altered by AD and Met alone or in combination. Our novel mechanistic studies provide evidence for an important role for IL1β in colon cancer and suggest that AD and/or Met might be useful agents in the management or chemoprevention of IL1β-induced colon carcinogenesis.
脂联素 (AD) 和二甲双胍 (Met) 都被提议下调结肠癌细胞的增殖，但它们的作用是否具有加性尚未得到研究。人类的遗传研究表明白细胞介素 1β (IL1β) 在癌症发病机制中具有重要作用。IL1β 有助于结肠癌发展的直接证据尚未得到充分证实，也没有先前的研究评估 IL1β 如何与 AD 和/或 Met 相互作用，以调节人类和小鼠结肠癌细胞的恶性潜能和细胞内信号通路。我们进行了体外研究，使用人类 (LoVo) 和小鼠 (MCA38) 结肠癌细胞系，评估 AD 和 Met 单独或联合使用是否可能拮抗 IL1β 调节的人类和小鼠结肠癌细胞系中的恶性潜能。IL1β 增加了恶性潜能，并调节了人类和小鼠结肠癌细胞系中肿瘤抑制因子 (p53) 和细胞周期调节基因 (p21、p27 和细胞周期蛋白 E2) 的表达。AD 和/或 Met 的联合给药逆转了这些效应，并以 STAT3 和 AMPK/LKB1 依赖性的方式使这些效应相加。我们还通过荧光激活细胞分选分析观察到，IL1β 调节的细胞周期进程被 AD 和 Met 单独或联合改变。我们的新机制研究为 IL1β 在结肠癌中的重要作用提供了证据，并表明 AD 和/或 Met 可能是管理或预防 IL1β 诱导的结肠癌发生的有用药物。
