Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao 266061, Qingdao Cancer Institute, Qingdao University, Qingdao 266061, China.
Department of Chinese Medicine, Qingdao No. 6 People's Hospital, Qingdao, China.
Biochem Biophys Res Commun. 2021 Jul 23;563:1-7. doi: 10.1016/j.bbrc.2021.05.068. Epub 2021 May 27.
The SH2 domain-containing phosphatase 2 (SHP2) is a widely expressed protein tyrosine phosphatase, and it is proposed to act as an oncogenic protein. SHP2 is also engaged in drug resistance of a variety of cancers. However, the role of SHP2 in the proliferation and drug resistance of colon cancer cells remains elusive. In this work we determined the effect of SHP2 expression on colon cancer cell proliferation and resistance to oxaliplatin (L-OHP), a commonly used drug in the clinic. Our results show that knockdown of SHP2 decreased and overexpression of SHP2 increased the proliferation of SW480 cells, respectively. Knockdown of SHP2 increased, and overexpression of SHP2 decreased apoptosis of the cells. We selected oxaliplatin-resistant SW480(SW480/L-OHP) and HCT116(HCT116/L-OHP) cells and found that the SHP2 protein level was raised in these drug-resistant cells. The upregulated SHP2 contributed to oxaliplatin resistance of the cells, as knockdown of SHP2 decreased the IC of oxaliplatin and abated proliferation and survival of SW480/L-OHP and HCT116/L-OHP cells in the presence of oxaliplatin. Also, SW480/L-OHP and HCT116/L-OHP cells had increased phosphorylation of AKT and ERK. Inhibition of AKT, ERK, or SHP2 sensitized SW480/L-OHP and HCT116/L-OHP cells to oxaliplatin. Our results indicate that SHP2 contributes oxaliplatin resistance through AKT and ERK. These results also suggest that SHP2-targeting is a potential strategy for overcoming oxaliplatin resistance of colon cancer cells.
SH2 结构域含有磷酸酶 2（SHP2）是一种广泛表达的蛋白酪氨酸磷酸酶，被认为是一种致癌蛋白。SHP2 还参与多种癌症的耐药性。然而，SHP2 在结肠癌细胞增殖和耐药性中的作用仍不清楚。在这项工作中，我们确定了 SHP2 表达对结肠癌细胞增殖和对奥沙利铂（L-OHP）耐药性的影响，奥沙利铂是临床上常用的药物。我们的结果表明，SHP2 敲低分别降低和过表达增加了 SW480 细胞的增殖。SHP2 敲低增加，而过表达减少了细胞的凋亡。我们选择了奥沙利铂耐药的 SW480（SW480/L-OHP）和 HCT116（HCT116/L-OHP）细胞，发现这些耐药细胞中的 SHP2 蛋白水平升高。上调的 SHP2 有助于细胞对奥沙利铂的耐药性，因为 SHP2 敲低降低了奥沙利铂的 IC 并减弱了奥沙利铂存在时 SW480/L-OHP 和 HCT116/L-OHP 细胞的增殖和存活。此外，SW480/L-OHP 和 HCT116/L-OHP 细胞中 AKT 和 ERK 的磷酸化增加。AKT、ERK 或 SHP2 的抑制使 SW480/L-OHP 和 HCT116/L-OHP 细胞对奥沙利铂敏感。我们的结果表明，SHP2 通过 AKT 和 ERK 促进奥沙利铂耐药性。这些结果还表明，针对 SHP2 是克服结肠癌细胞奥沙利铂耐药性的一种潜在策略。
