title: Enhancement of tumor initiation and expression of KCNMA1, MORF4L2 and ASPM genes in the adenocarcinoma of lung xenograft after vorinostat treatment.
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 ALDHbr 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 ALDHbr cells. These findings suggested that SAHA treatment created a more drug-resistant state in residual ALDHbr cells. The in vivo imaging technique may facilitate searching and characterization of CSCs.
authors: Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan.
authors: Wei-Ying
authors: WY
authors: Kuo
authors: Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, Taiwan.
authors: Chun-Yi
authors: CY
authors: Wu
authors: Molecular and Genetic Imaging Core/Taiwan Mouse Clinic, National Comprehensive Mouse Phenotyping and Drug Testing Center, Taipei, Taiwan.
authors: Luen
authors: L
authors: Hwu
authors: Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan.
authors: Jhih-Shian
authors: JS
authors: Lee
authors: Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan.
authors: Cheng-Han
authors: CH
authors: Tsai
authors: Department of Electrical Engineering, Chung Yuan Christian University, Chungli, Taiwan.|Holistic Medical Device Development Center, Chung Yuan Christian University, Chungli, Taiwan.
authors: Kang-Ping
authors: KP
authors: Lin
authors: Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan.
authors: Hsin-Ell
authors: HE
authors: Wang
authors: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors: Teh-Ying
authors: TY
authors: Chou
authors: Department of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors: Chun-Ming
authors: CM
authors: Tsai
authors: Department of Biomedical Engineering and Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
authors: Juri
authors: J
authors: Gelovani
authors: Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan.|Molecular and Genetic Imaging Core/Taiwan Mouse Clinic, National Comprehensive Mouse Phenotyping and Drug Testing Center, Taipei, Taiwan.|Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.|National PET/Cyclotron Center and Department of Nuclear Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Ren-Shyan
authors: RS
authors: Liu
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000444:Aldehyde Dehydrogenase / Q000032:analysis; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000066673:Cell Self Renewal / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D017930:Genes, Reporter; D064593:Heterografts; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000096:biosynthesis* / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection; D000077337:Vorinostat
chemical_list: C467202:ASPM protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C494841:KCNMA1 protein, human; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; C491669:MORF4L2 protein, human; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D000077337:Vorinostat; D000444:Aldehyde Dehydrogenase
keywords: ALDH activity; cancer stem cells; lung cancer; suberoylanilide hydroxamic acid (SAHA)