ADAM9 mediates Cisplatin resistance in gastric cancer cells through DNA damage response pathway

Abstract

Gastric cancer is one of the most common malignant tumors in the world. The occurrence of chemotherapy resistance seriously affects the survival and prognosis of middle and advanced patients. Enhancing DNA repair ability is one of the important mechanisms of chemotherapy resistance. ADAM9, a member of the disintegrin and metalloproteinase family, is involved in many biological processes, such as tumor cells proliferation, apoptosis, invasion and migration, vascular invasion, and drug resistance. In this study, we found that the high expression of ADAM9 in gastric cancer tissues was associated with a variety of clinicopathological factors and poor prognosis in patients. Gastric cancer cells with high ADAM9 expression reduced sensitivity to Cisplatin, decreased DNA damage, increased expression of ATM and CHK2, the key proteins in DNA damage repair pathway, and improved cancer cells survival rate. Further studies showed that the expression of ADAM9 was selectively interfered with gastric cancer cells, the expression levels of ATM and CHK2 were decreased, while the expression of damage protein γ-H2AX was significantly increased, the degree of DNA damage was increased, and the sensitivity of gastric cancer cells to Cisplatin was significantly enhanced. It is suggested that ADAM9 is involved in Cisplatin resistance in gastric cancer cells, and its mechanism is related to the activation of ATM-CHK2 pathway in DNA damage repair. These data demonstrate that ADAM9 plays a pro-cancer role and mediates Cisplatin resistance in gastric cancer, which may be a new target to overcome chemotherapy resistance.

Keywords: ADAM9; AGS; Cisplatin; DNA damage repair; Drug resistance; Gastric cancer.