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

Abstract

Background/Aim: 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. Materials and Methods: 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. Results: CaCC inh -A01 decreased chloride currents. CaCC inh -A01 and T16 inh -A01 reduced GIST cell viability and CaCC inh -A01 affected cell cycle distribution leading to G 1 cell-cycle arrest. CaCC inh -A01 also increased the sub-G 1 phase population, indicative of apoptosis, in GIST882. CaCC inh -A01 strongly reduced the colony forming ability of the cells, whereas T16 inh -A01 did not. Conclusion: DOG1 inhibition has antitumoral effects in GIST cells in vitro, and could potentially serve as a target for GIST therapy.

ANO1: More Than Just Calcium-Activated Chloride Channel in Cancer

“…The above data indicate that ANO1 may be involved in the cell cycle process, but it remains to be clarified how ANO1 induces tumor cell cycle arrest. Existing studies have found that the ANO1 inhibitor Caccinh-A01 may reduce the chloride current in gastric cancer cells and cause the G1 phase of the cell cycle block ( 72 ). At the same time, research on colorectal cancer found that cyclin D1 protein expression was positively correlated with ERK1/2 and ANO1.ANO1 inhibits G1 to S phase progression by down-regulating the expression of the ANO1, which is consistent with the decreased expression of cyclin D1 ( 28 ).…”

DOG1 is commonly expressed in pancreatic adenocarcinoma but unrelated to cancer aggressiveness

“…Due to the general role of DOG1 overexpression in tumorigenesis and progression as well as the absence or low level of DOG1 expression in most normal tissues, DOG1 may also represent a suitable drug target. Studies have shown that partial or total inhibition of DOG1 with T16Ainh-A01 and CaCCinh-A01 leads to reduced channel activity, cell viability, cell proliferation, cell migration, increased apoptosis, and cell cycle arrest in G0/G1 phase in GIST and cancer cells of the breast, bladder, head and neck, and esophagus in vitro ( Frobom et al, 2019 ; Guan et al, 2016 ; Berglund et al, 2014 ; Duvvuri et al, 2012 ; Britschgi et al, 2013 ) and reduced tumor growth of lung, breast, and head and neck carcinomas in vivo ( Hu, Zhang & Jiang, 2019 ; Kulkarni et al, 2017 ). In addition, three studies showed that combined inhibition of DOG1 and EGFR or DOG1 and HER2 leads to reduced cell growth in a cooperative manner and that DOG1 inhibition can reverse resistance to EGFR or HER2 therapies in vitro and in vivo ( Kulkarni et al, 2017 ; Fujimoto et al, 2017 ; Bill et al, 2015 ).…”

Tumor genotype, location, and malignant potential shape the immunogenicity of primary untreated gastrointestinal stromal tumors

“…ANO1-encoded protein, anoctamin-1, is typically expressed by GISTs, with a diffuse staining pattern generally stronger in KIT-mutated and NF1-mutated tumors (39,40). Anoctamin-1 is a calcium-activated anion channel whose chemical inhibition affects GIST cell proliferation and viability (65). Recent evidence also implicates this molecule in chemokine signaling (41).…”

“…Finally, the intriguing correlation between ANO1 expression and degree of immune infiltration points to an additional possible element of vulnerability. Several compounds have demonstrated inhibitory activity toward anoctamin-1, including FDA-approved drugs (65,73,74), and chemical inhibition of anoctamin-1 has been shown to affect GIST cell proliferation and survival (65). It would be interesting to evaluate the effect of these compounds on cytokine secretion.…”