title: Aldehyde dehydrogenase activity plays no functional role in stem cell-like properties in anaplastic thyroid cancer cell lines.
abstract: Recent studies have revealed that aldehyde dehydrogenase (ALDH) is a candidate marker for thyroid cancer stem cells, although its activity is flexible. The goal of this study is to clarify the functional significance of ALDH enzymatic activity on thyroid cancer stem cells properties in anaplastic thyroid cancer cell lines. In vitro sphere formation assay was used to judge the stemness of 4 anaplastic thyroid cancer cell lines (FRO, ACT1, 8505C, and KTC3). Two well-known ALDH inhibitors, N,N-diethylaminobenzaldehyde (DEAB) and disulfiram (DS), were first used. DEAB (50 μM) almost completely suppressed ALDH activity without affecting cell proliferation or spherogenicity. Lack of effect of ALDH suppression on spherogenicity was confirmed using shRNA for ALDH1A3, an ALDH isozyme predominantly expressed in anaplastic thyroid cancer cell lines. In contrast, an ALDH2 inhibitor DS (1 μM) inhibited spherogenicity but did not inhibit ALDH1A3 activity. Based on the recent article from another group reporting the importance of sonic hedgehog (Shh) signaling in ALDH activity and spherogenicity in thyroid cancer, the effects of the Shh inhibitor cyclopamine were also studied. Like DS, cyclopamine (1 μM) decreased spherogenicity but not ALDH activity. Finally, exogenous expression of ALDH1A3 in otherwise ALDH-TPC1 cells (a papillary thyroid cancer cell line) revealed no effect on spherogenicity. In conclusion, we here show no functional role for ALDH activity in thyroid thyroid cancer stem cells properties. That is, ALDH activity and spherogenicity are clearly dissociable. Further understanding of thyroid cancer stem cells biology in thyroid cancers remains necessary for the future development of thyroid thyroid cancer stem cells-targeted therapies.
authors.affiliation: Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Shimamura
authors.affiliation: Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kurashige
authors.affiliation: Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.
authors.forename: Norisato
authors.initials: N
authors.lastname: Mitsutake
authors.affiliation: Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. nagayama@nagasaki-u.ac.jp.
authors.forename: Yuji
authors.identifier: http://orcid.org/0000-0002-5058-9349
authors.initials: Y
authors.lastname: Nagayama
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004221:Disulfiram / Q000494:pharmacology; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D065646:Thyroid Carcinoma, Anaplastic / Q000201:enzymology* / Q000473:pathology; D010128:p-Aminoazobenzene / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C007368:C.I. Solvent Yellow 56; D010128:p-Aminoazobenzene; D004221:Disulfiram
keywords: Aldefluor assay; Aldehyde dehydrogenase; Cancer stem cells; Spherogenicity; Thyroid cancer