AKT inhibition is an effective treatment strategy in ARID1A-deficient gastric cancer cells
Authors Lee D, Yu EJ, Ham I, Hur H, Kim Y
Received 14 April 2017
Accepted for publication 8 July 2017
Published 22 August 2017 Volume 2017:10 Pages 4153—4159
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Narasimha Reddy Parine
Peer reviewer comments 2
Editor who approved publication: Dr Jianmin Xu
Dakeun Lee,1 Eun Ji Yu,1 In-Hye Ham,2,3 Hoon Hur,2,3 You-Sun Kim4,5
1Department of Pathology, Ajou University School of Medicine, Suwon, Republic of Korea; 2Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea; 3Brain Korea 21 Plus Research Center for Biomedical Sciences, Ajou University, Suwon, Republic of Korea; 4Department of Biochemistry, Ajou University School of Medicine, Suwon, Republic of Korea; 5Department of Biomedical Sciences, Graduate School, Ajou University, Suwon, Republic of Korea
Background: The At-rich interactive domain 1A (ARID1A) is frequently mutated in gastric cancers (GCs) with a poor prognosis. Growing evidence indicates that loss of ARID1A expression leads to activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway by AKT phosphorylation. We aim to investigate the different sensitivity for the AKT inhibitor in ARID1A-deficient GC cells.
Methods: After transfection using siRNA or shRNA, the effect of ARID1A knockdown on the PI3K/AKT signaling pathway was evaluated by Western blot analysis. ARID1A-knockdown cells were treated with AKT inhibitor (GSK690693), 5-fluorouracil, or cisplatin, alone or in combination. Viability and apoptosis were analyzed using EZ-CYTOX cell viability assay and flow cytometry, respectively.
Results: ARID1A depletion accelerated the phosphorylation of AKT and S6 in a dose-dependent manner and led to an increased proliferation of MKN-1, MKN-28, and KATO-III GC cells (P<0.001). ARID1A-deficient cells were more vulnerable to GSK690693 in comparison to the controls (P<0.001), even at very low doses. Flow cytometry confirmed the increased apoptosis in ARID1A-deficient cells treated with GSK690693 (0.01 µmol/L; P<0.001). In contrast to our expectations, ARID1A depletion did not cause resistance to 5-fluorouracil or cisplatin. Addition of GSK690693 to the conventional chemotherapy induced more decreased cell viability in ARID1A-knockdown cells (P<0.01).
Conclusion: Loss of ARID1A expression is a surrogate marker for the activation of the AKT signaling pathway and is also a reliable biomarker to predict the response for the AKT inhibitor. We anticipate that appropriate patient selection based on ARID1A expression in the tumor tissue will increase the drug sensitivity for the AKT inhibition and improve the clinical outcome.
Keywords: gastric cancer, ARID1A, AKT inhibitor, chemotherapy
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