title: Phenotypic screening of a library of compounds against metastatic and non-metastatic clones of a canine mammary gland tumour cell line.
abstract: Metastases are associated with a poor prognosis for canine mammary gland tumours (CMGTs). Metastatic and non-metastatic clones were isolated previously from a single malignant CMGT cell line. The difference in metastatic potential between the two cell lines was hypothesised to be associated with distinct cellular signalling. The aim of this study was to screen for compounds that specifically target metastatic cells in order to improve CMGT therapeutic outcomes. The two clonal cell lines were characterised by transcriptome analysis and their sensitivity to a library of 291 different compounds was compared. The metastatic clone exhibited elevated expression of molecules associated with degradation of the extracellular matrix, epithelial-mesenchymal transition and cancer stem cell phenotype. This was confirmed using a matrigel invasion assay and by assessment of aldehyde dehydrogenase activity. The mitochondrial respiratory chain complex inhibitors (MRCIs; rotenone, antimycin and oligomycin) significantly inhibited the growth of the metastatic clone. Although MRCIs similarly depleted mitochondrial ATP in both clones, the subsequent cellular response was different, with toxicity to the metastatic clone being independent of AMP-activated protein kinase activity. The results of this study suggest a potential utility of MRCIs as anti-tumour agents against metastatic CMGTs. Further studies are needed to investigate the clinical utility of MRCIs and to determine the association between MRCI sensitivity and malignancy.
authors.affiliation: Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Saeki
authors.affiliation: Department of Medical Genome Science, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa 277-8561, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Veterinary Pathology, Nippon Veterinary and Life Science University, 1-7-1 Kyonan-cho, Musashino, Tokyo 180-8602, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Michishita
authors.affiliation: Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tsuboi
authors.affiliation: Department of Medical Genome Science, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa 277-8561, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Sugano
authors.affiliation: Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Yoshitake
authors.affiliation: Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Murai
authors.affiliation: Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: S M
authors.initials: SM
authors.lastname: Ong
authors.affiliation: Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Saito
authors.affiliation: Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Fujita
authors.affiliation: Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Nishimura
authors.affiliation: Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan. Electronic address: anakaga@mail.ecc.u-tokyo.ac.jp.
authors.forename: T
authors.initials: T
authors.lastname: Nakagawa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002999:Clone Cells; D004283:Dog Diseases / Q000188:drug therapy*; D004285:Dogs; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy*; D059467:Transcriptome
chemical_list: D000970:Antineoplastic Agents
keywords: Canine; Chemotherapy; Compound screening; Mammary gland tumour cell lines; Metastases; Mitochondrial respiratory chain complex inhibitors