Dept. of Neuroscience and Cell Biology, Univ. of Texas Medical Branch, 10.104 Medical Research Bldg., 301 Univ. Blvd., Route 1043, Galveston, TX 77555-1043, USA.
Am J Physiol Gastrointest Liver Physiol. 2010 Apr;298(4):G551-62. doi: 10.1152/ajpgi.00497.2009. Epub 2010 Feb 4.
Progastrin and insulin-like growth factors (IGFs) stimulate hyperproliferation of intestinal epithelial cells (IECs) via endocrine/paracrine routes; hyperproliferation is a known risk factor for colon carcinogenesis. In the present study, inhibitory potency of curcumin in the presence or absence of progastrin and/or IGF-II was examined. Progastrin and IGF-II significantly increased proliferation of an immortalized IEC cell line, IEC-18, whereas curcumin decreased the proliferation in a dose-dependent manner. IGF-II was significantly more effective than progastrin in reversing antiproliferative effects of curcumin and reversed proapoptotic effects of curcumin by >80%; progastrin was relatively ineffective toward reversing proapoptotic effects of curcumin. IEC-18 clones were generated to overexpress either progastrin (IEC-PG) or hIGF-II (IEC-IGF). Proliferation of IEC-PG and IEC-IGF clones was increased, compared with that of control clones. Curcumin significantly reduced proliferation of IEC-PG, but not IEC-IGF, clones. Similarly, a human colon cancer cell line, Caco-2 (which expresses autocrine IGF-II), was relatively resistant to inhibitory effects of curcumin. However, Caco-2 cells treated with anti-IGF-II-antibodies were rendered sensitive to inhibitory effects of curcumin. Significant differences in inhibitory potency of curcumin against PG- vs. IGF-II-stimulated growth of IEC-18 cells were not reflected by differences in curcumin-mediated inhibition of activated (phosphorylated) ERKs/IKK(alpha/beta)/p65NF-kappaB and c-Src in wild-type (wt)IEC-18 cells, in response to the two growth factors. Surprisingly, curcumin was almost ineffective in reducing IGF-II-stimulated activation of p38MAPK but significantly reduced progastrin-stimulated phosphorylation of p38. Treatment with a p38MAPK inhibitor resulted in loss of protective effects of IGF-II against inhibitory effects of curcumin. These novel findings suggest that growth factor profile of patients and tumors may dictate inhibitory potency of curcumin and that combination of curcumin + p38MAPK inhibitor may be required for reducing hyperproliferative or tumorigenic response of IECs to endocrine and autocrine IGFs.
胃泌素和胰岛素样生长因子（IGFs）通过内分泌/旁分泌途径刺激肠上皮细胞（IECs）的过度增殖；过度增殖是结直肠癌发生的已知危险因素。在本研究中，检测了姜黄素在存在或不存在胃泌素和/或 IGF-II 的情况下的抑制效力。胃泌素和 IGF-II 显著增加了永生化 IEC 细胞系 IEC-18 的增殖，而姜黄素则以剂量依赖性方式降低了增殖。IGF-II 在逆转姜黄素的抗增殖作用方面比胃泌素更有效，逆转姜黄素的促凋亡作用超过 80%；胃泌素在逆转姜黄素的促凋亡作用方面相对无效。生成了过表达胃泌素（IEC-PG）或 hIGF-II（IEC-IGF）的 IEC-18 克隆。与对照克隆相比，IEC-PG 和 IEC-IGF 克隆的增殖增加。姜黄素显著降低了 IEC-PG 克隆的增殖，但不降低 IEC-IGF 克隆的增殖。同样，表达自分泌 IGF-II 的人结肠癌细胞系 Caco-2 对姜黄素的抑制作用相对耐药。然而，用抗 IGF-II 抗体处理的 Caco-2 细胞对姜黄素的抑制作用变得敏感。PG- 与 IGF-II 刺激的 IEC-18 细胞生长的姜黄素抑制效力的显著差异并未反映在两种生长因子对 wtIEC-18 细胞中姜黄素介导的激活（磷酸化）ERK/IKK(alpha/beta)/p65NF-kappaB 和 c-Src 的抑制作用上。令人惊讶的是，姜黄素在降低 IGF-II 刺激的 p38MAPK 激活方面几乎无效，但显著降低了胃泌素刺激的 p38 磷酸化。用 p38MAPK 抑制剂处理会导致 IGF-II 对姜黄素抑制作用的保护作用丧失。这些新发现表明，患者和肿瘤的生长因子谱可能决定姜黄素的抑制效力，并且可能需要姜黄素+ p38MAPK 抑制剂的组合来降低 IEC 对内分泌和自分泌 IGF 的过度增殖或肿瘤发生反应。
