Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, Veterinary Research Building 410, College Station, TX 77843-4466, USA.
Mol Cancer Res. 2010 May;8(5):739-50. doi: 10.1158/1541-7786.MCR-09-0493. Epub 2010 Apr 20.
The epidermal growth factor receptor (EGFR) is an important chemotherapeutic target for tyrosine kinase inhibitors and antibodies that block the extracellular domain of EGFR. Betulinic acid (BA) and curcumin inhibited bladder cancer cell growth and downregulated specificity protein (Sp) transcription factors, and this was accompanied by decreased expression of EGFR mRNA and protein levels. EGFR, a putative Sp-regulated gene, was also decreased in cells transfected with a cocktail (iSp) containing small inhibitory RNAs for Sp1, Sp3, and Sp4, and RNA interference with individual Sp knockdown indicated that EGFR expression was primarily regulated by Sp1 and Sp3. BA, curcumin, and iSp also decreased phosphorylation of Akt in these cells, and downregulation of EGFR by BA, curcumin, and iSp was accompanied by induction of LC3 and autophagy, which is consistent with recent studies showing that EGFR suppresses autophagic cell death. The results show that EGFR is an Sp-regulated gene in bladder cancer, and drugs such as BA and curcumin that repress Sp proteins also ablate EGFR expression. Thus, compounds such as curcumin and BA that downregulate Sp transcription factors represent a novel class of anticancer drugs that target EGFR in bladder cancer cells and tumors by inhibiting receptor expression.
表皮生长因子受体 (EGFR) 是酪氨酸激酶抑制剂和抗体的重要化疗靶点，这些抑制剂和抗体可以阻断 EGFR 的细胞外结构域。白桦脂酸 (BA) 和姜黄素抑制膀胱癌细胞生长，并下调特异性蛋白 (Sp) 转录因子，这伴随着 EGFR mRNA 和蛋白水平的降低。EGFR 是一个假定的 Sp 调节基因，在转染含有 Sp1、Sp3 和 Sp4 的小干扰 RNA 鸡尾酒 (iSp) 的细胞中也减少，并且 Sp 敲低的单个 RNA 干扰表明 EGFR 表达主要受 Sp1 和 Sp3 调节。BA、姜黄素和 iSp 也降低了这些细胞中 Akt 的磷酸化，BA、姜黄素和 iSp 下调 EGFR 的同时诱导 LC3 和自噬，这与最近的研究表明 EGFR 抑制自噬性细胞死亡一致。结果表明，EGFR 是膀胱癌中的 Sp 调节基因，像 BA 和姜黄素这样抑制 Sp 蛋白的药物也能消除 EGFR 的表达。因此，像姜黄素和 BA 这样的下调 Sp 转录因子的化合物代表了一类新型的抗癌药物，通过抑制受体表达，针对膀胱癌细胞和肿瘤中的 EGFR。
