Enhancement of tumor initiation and expression of KCNMA1, MORF4L2 and ASPM genes in the adenocarcinoma of lung xenograft after vorinostat treatment

// Wei-Ying Kuo 1,* , Chun-Yi Wu 2,* , Luen Hwu 3 , Jhih-Shian Lee 1 , Cheng-Han Tsai 1 , Kang-Ping Lin 4,5 , Hsin-Ell Wang 1 , Teh-Ying Chou 6 , Chun-Ming Tsai 7 , Juri Gelovani 8 , Ren-Shyan Liu 1,3,6,9 1 Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan 2 Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, Taiwan 3 Molecular and Genetic Imaging Core/Taiwan Mouse Clinic, National Comprehensive Mouse Phenotyping and Drug Testing Center, Taipei, Taiwan 4 Department of Electrical Engineering, Chung Yuan Christian University, Chungli, Taiwan 5 Holistic Medical Device Development Center, Chung Yuan Christian University, Chungli, Taiwan 6 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan 7 Department of Medicine, National Yang-Ming University, Taipei, Taiwan 8 Department of Biomedical Engineering and Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA 9 National PET/Cyclotron Center and Department of Nuclear Medicine, Taipei Veterans General Hospital, Taipei, Taiwan * These authors contributed equally to this study Correspondence to: Ren-Shyan Liu, email: // Keywords : Lung cancer, ALDH activity, cancer stem cells, suberoylanilide hydroxamic acid (SAHA) Received : November 25, 2014 Accepted : February 12, 2015 Published : March 12, 2015 Abstract Cancer stem cells (CSCs) are usually tolerant to chemotherapy and radiotherapy and associated with tumor relapse. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDACI), is currently being used in clinical trials of lung cancer. However, SAHA facilitates the formation of induced pluripotent stem cells from somatic cells. We hypothesized that SAHA would mediate the CSCs properties and subsequently confer a more malignant phenotype in lung cancer. Transfected H1299 lung cancer cells, which stably expresses a triple fused reporter gene (DsRedm-Fluc-tTKsr39) under the control of CMV promoter was used to establish a xenograft mouse model. After the treatment of SAHA, H1299 cell line and tumor xenografts were sorted by fluorescence-activated cell sorting (FACS) based on aldehyde dehydrogenase (ALDH) activity. We found that SAHA could suppress the growth of xenografted H1299 tumors with decreased proportion of ALDH br lung cancer cells indicating that SAHA may target CSCs. However, SAHA significantly enhanced the tumor initiating capacity and the expression of malignant genes such as KCNMA1, MORF4L2 and ASPM in the remaining living ALDH br cells. These findings suggested that SAHA treatment created a more drug-resistant state in residual ALDH br cells. The in vivo imaging technique may facilitate searching and characterization of CSCs.