Biochemical Inhibition of DOG1/TMEM16A Achieves Antitumoral Effects in Human Gastrointestinal Stromal Tumor Cells In Vitro

• Published in: Anticancer research 2019-07, Vol.39 (7), p.3433-3442
• Main Authors: Fröbom, Robin, Sellberg, Felix, Xu, Cheng, Zhao, Allan, Larsson, Catharina, Lui, Wenn-Onn, Nilsson, Inga-Lena, Berglund, Erik, Bränström, Robert
• Format: Article
• Language: English
• Subjects: Anoctamin-1 - antagonists & inhibitors; Anoctamin-1 - physiology; Anticancer properties; Apoptosis; Calcium; Calcium chloride; cancer; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Cell viability; Chloride channels (calcium-gated); Chloride currents; Chloride ions; Colonies; DOG1; G1 phase; Gastrointestinal cancer; Gastrointestinal Neoplasms - drug therapy; Gastrointestinal Neoplasms - physiopathology; Gastrointestinal stromal tumors; Gastrointestinal Stromal Tumors - drug therapy; Gastrointestinal Stromal Tumors - physiopathology; GIST; Humans; Inhibition; ion channel; Ion channels; Medicin och hälsovetenskap; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - physiology; Pyrimidines - pharmacology; Thiazoles - pharmacology; Thiophenes - pharmacology; TMEM16A; Tumor cells; Tumors
• ISSN: 0250-7005; 1791-7530; 1791-7530
• DOI: 10.21873/anticanres.13489

DOG1 is a calcium-activated chloride channel that has gained attention as a promising drug target due to its involvement in several processes essential for tumor development and progression. DOG1 is overexpressed in >95% of gastrointestinal stromal tumors (GIST). The aim was to determine DOG1 inhibition antitumoral effects on GIST. Human GIST (GIST-T1 and GIST882) cell lines were used to study the effect of DOG1 inhibitors on chloride currents, viability, colony formation, and cell cycle. CaCC -A01 decreased chloride currents. CaCC -A01 and T16 -A01 reduced GIST cell viability and CaCC -A01 affected cell cycle distribution leading to G cell-cycle arrest. CaCC -A01 also increased the sub-G phase population, indicative of apoptosis, in GIST882. CaCC -A01 strongly reduced the colony forming ability of the cells, whereas T16 -A01 did not. DOG1 inhibition has antitumoral effects in GIST cells in vitro, and could potentially serve as a target for GIST therapy.