Tohoku J. Exp. Med., 2018 February, 244(2)

Potential Role of ASC, a Proapoptotic Protein, for Determining the Cisplatin Susceptibility of Lung Cancer Cells

TAKAO SAKAIZAWA,^1,2,3 TOMIO MATSUMURA,² CHIFUMI FUJII,^2,4 SHIGEAKI HIDA,^2,5 MASAYUKI TOISHI,^1,3 TAKAYUKI SHIINA,^1,6 KAZUO YOSHIDA,^1,7 KAZUTOSHI HAMANAKA,¹ KEN-ICHI ITO¹ and SHUN'ICHIRO TANIGUCHI^2,4,8

¹Division of Breast, Endocrine and Respiratory Surgery, Department of Surgery (II), Shinshu University School of Medicine, Matsumoto, Nagano, Japan
²Department of Molecular Oncology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan
³Department of Chest and Breast Surgery, Nagano Municipal Hospital, Nagano, Nagano, Japan
⁴Department of Advanced Medicine for Health Promotion, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Nagano, Japan
⁵Department of Molecular and Cellular Health Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan
⁶Department of Thoracic Surgery, Ina Central Hospital, Ina, Nagano, Japan
⁷Department of Thoracic Surgery, Suwa Red Cross Hospital, Suwa, Nagano, Japan
⁸Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Nagano, Japan

Primary lung cancer is the most frequent cause of cancer-related deaths worldwide. Cisplatin has been used as a key drug in the treatment for patients with lung cancer; however, most of the patients failed to respond to cisplatin within several months, and the mechanisms underlying the cisplatin resistance have not been fully elucidated. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is a key adaptor protein in the formation of inflammasomes. ASC is also involved in apoptotic signaling. Importantly, ASC expression is decreased in lung cancer and various cancers, but its precise function in tumor progression remains unknown. To explore the hitherto unknown role of ASC in lung cancer, we initially searched for lung cancer cell lines with higher expression levels of ASC using Cancer Cell Line Encyclopedia (CCLE) database, thereby identifying the A549 human non-small cell lung cancer cell line. Accordingly, with retroviral shRNA, the expression of ASC was forced to decrease in A549 cells. Stable ASC-knockdown cells, thus established, showed the increased activities of proliferation, motility, and invasion, compared with control cells. Importantly, ASC-knockdown cells also became resistant to cisplatin, but not to other anti-cancer agents, 5-fluorouracil and paclitaxel. Bcl-2 and phospho-Src levels were increased in ASC-knockdown cells. A Bcl-2 inhibitor, ABT-199, induced an apoptotic response in ASC-knockdown cells, and dasatinib, a Src inhibitor, blocked cell invasiveness. Thus, ASC may be involved in tumor suppression and cell death via Bcl-2 and pSrc. Targeting Bcl-2 and Src in ASC-downregulated populations of lung cancer may improve treatment outcome.

keywords —— Keywords: ASC; Bcl-2; cisplatin resistance; lung cancer; Src

© 2018 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2018, 244, 133-144

Correspondence: Takao Sakaizawa, Department of Chest and Breast Surgery, Nagano Municipal Hospital, 1333-1 Tomitake, Nagano, Nagano 381-8551, Japan.

e-mail: takao_sakaizawa@hospital.nagano.nagano.jp