Wu Chuanqing, Hu Shaobo, Cheng Ji, Wang Guobin, Tao Kaixiong
Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
Exp Ther Med. 2017 May;13(5):2529-2536. doi: 10.3892/etm.2017.4282. Epub 2017 Mar 29.
The sonic hedgehog (Shh) pathway has been proven to be involved in embryonic development and cancer growth. GDC-0449, an antagonist of the hedgehog signaling receptor Smoothened (Smo), was recently approved by the US Food and Drug Administration as a prescription for skin basal cell carcinoma. However, the efficacy of GDC-0449 in the treatment of colon cancer and other malignancies, such as basal cell carcinoma and pancreatic cancer, has remained to be proven. The present study assessed the effect of GDC-0449 on the colon cancer cell lines Caco-2 and Ht-29. A Cell Counting Kit-8 assay was applied to assess the cell proliferation rate and apoptosis was tested by flow cytometry. Reverse-transcription quantitative PCR and western blot analysis were used for analyzing expression levels of target genes. Cell proliferation was inhibited, while apoptosis was increased by GDC-0449, whereas the expression of B-cell lymphoma 2 (Bcl-2), a downstream target of Shh signaling, was decreased. Consistent with the inhibition of Gli1 expression, the cancer stem cell markers CD44 and ALDH were decreased in the presence of GDC-0449. In conclusion, GDC-0449 was shown to inhibit the replication of colon cancer cells and trigger apoptosis through downregulating Bcl-2. This may also influence the stemness of cancer stem cells as indicated by the decreased stem cell surface markers.
已证实音猬因子（Shh）信号通路参与胚胎发育和癌症生长。GDC - 0449是刺猬信号受体平滑肌瘤（Smo）的拮抗剂，最近被美国食品药品监督管理局批准用于治疗皮肤基底细胞癌。然而，GDC - 0449在治疗结肠癌及其他恶性肿瘤（如基底细胞癌和胰腺癌）方面的疗效仍有待证实。本研究评估了GDC - 0449对结肠癌细胞系Caco - 2和Ht - 29的作用。采用细胞计数试剂盒 - 8法评估细胞增殖率，通过流式细胞术检测细胞凋亡情况。运用逆转录定量PCR和蛋白质印迹分析来分析靶基因的表达水平。GDC - 0449抑制细胞增殖，同时增加细胞凋亡，而Shh信号的下游靶点B细胞淋巴瘤2（Bcl - 2）的表达降低。与Gli1表达受到抑制一致，在GDC - 0449存在的情况下，癌症干细胞标志物CD44和醛脱氢酶（ALDH）减少。总之，研究表明GDC - 0449通过下调Bcl - 2抑制结肠癌细胞的复制并引发细胞凋亡。这也可能会影响癌症干细胞的干性，如干细胞表面标志物减少所示。
