Schmelz Eva M, Xu Hu, Sengupta Radha, Du Jianhua, Banerjee Sanjeev, Sarkar Fazlul H, Rishi Arun K, Majumdar Adhip P N
Department of Nutrition and Food Science, Wayne State University, Detriot, Michigan 48220, USA.
Cancer Res. 2007 Jun 1;67(11):5389-96. doi: 10.1158/0008-5472.CAN-07-0536.
A role of the epidermal growth factor receptor (EGFR) family has been suggested in colon cancer etiology, progression, and/or severity. Our recently identified pan-erbB inhibitor EGFR-related protein (ERRP) targets EGFRs by attenuating their activation and subsequent signaling leading to cellular growth inhibition. In the present study, we evaluated the therapeutic effectiveness of ERRP on early and intermediate stages of colon cancer by examining regression of chemically induced aberrant crypt foci (ACF) in the colon of CF1 mice and intestinal adenomas in APC(Min+/-) (Min) mice. After formation of ACF or adenomas, the mice were injected (i.p.) with ERRP (50 microg/mouse) for 10 consecutive days. This treatment significantly reduced the number of ACF from 25.0 +/- 3.0 (controls) to 14.9 +/- 1.6 (ERRP-treated; P = 0.011) and also reduced their size (P < 0.01). In Min mice, ERRP caused the regression of adenomas throughout the small intestine (P < 0.05) and reduced their size (P < 0.001). This could partly be attributed to inhibition of proliferation and stimulation of apoptosis in the intestinal mucosa and was associated with decreased activation of several EGFR family members, suppression of downstream effector nuclear factor kappaB and down-regulation of cyclooxygenase-2. ERRP-induced attenuation of EGFR activation could be due to increased sequestration of the ligand(s) by ERRP, rendering them unavailable for binding to and activation of the receptor. In conclusion, our data show that ERRP is effective in regressing both early and intermediate intestinal lesions and could be an effective therapeutic agent for colon cancer.
表皮生长因子受体（EGFR）家族在结肠癌的病因、进展和/或严重程度方面可能发挥作用。我们最近鉴定出的泛erbB抑制剂表皮生长因子受体相关蛋白（ERRP）通过减弱EGFR的激活及其随后导致细胞生长抑制的信号传导来靶向EGFR。在本研究中，我们通过检查CF1小鼠结肠中化学诱导的异常隐窝灶（ACF）的消退以及APC（Min+/-）（Min）小鼠肠道腺瘤的消退，评估了ERRP对结肠癌早期和中期的治疗效果。在ACF或腺瘤形成后，给小鼠腹腔注射ERRP（50微克/小鼠），连续注射10天。这种治疗显著减少了ACF的数量，从25.0±3.0（对照组）降至14.9±1.6（ERRP治疗组；P = 0.011），并且还减小了其大小（P < 0.01）。在Min小鼠中，ERRP导致整个小肠腺瘤的消退（P < 0.05）并减小了它们的大小（P < 0.001）。这部分可归因于对肠黏膜增殖的抑制和凋亡的刺激，并且与几种EGFR家族成员的激活减少、下游效应物核因子κB的抑制以及环氧合酶-2的下调有关。ERRP诱导的EGFR激活减弱可能是由于ERRP对配体的螯合增加，使其无法与受体结合并激活受体。总之，我们的数据表明ERRP在消退早期和中期肠道病变方面有效，并且可能是结肠癌的一种有效治疗剂。
