title: Chemoresistance to concanamycin A1 in human oral squamous cell carcinoma is attenuated by an HDAC inhibitor partly via suppression of Bcl-2 expression.
abstract: V-ATPase is involved in the acidification of the microenvironment around/in solid tumors, such as oral squamous cell carcinoma (OSCC). V-ATPase is thought to induce tumor invasion and multi-drug resistance in several malignant tumors, and it also contributes to maintaining the intracellular pH under an acidic microenvironment by inducing proton extrusion into the extracellular medium. However, there is little information regarding the effects of V-ATPase inhibitors on OSCCs. In this study, the effects of a V-ATPase inhibitor, concanamycin A1 (CMA), on the proliferation and apoptosis of OSCC were investigated in vitro. We used four OSCC cell lines, MISK81-5, SAS, HSC-4 and SQUU-B. Acridine orange staining revealed that the red fluorescence was reduced in all of the low concentration CMA-treated OSCC cells, indicating that the acidification of vesicular organelles in the OSCCs was prevented by the treatment with low-concentration of CMA. CMA treatment induced apoptosis in MISK81-5, SAS and HSC-4 cells, but not in SQUU-B cells. The p-p38 expression was not altered in CMA-treated SQUU-B cells, but their levels were increased in the other cells. The Bax/Bcl-2 ratio in CMA-treated SQUU-B cells was dramatically decreased in comparison with that in the other cell lines treated with CMA. However, when the SQUU-B cells were treated with CMA and a histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), the SQUU-B cells became more susceptible to the CMA-induced apoptosis. SAHA treatment led to a significantly decrease in the Bcl-2 expression in CMA-treated SQUU-B cells, resulting in a dramatically increased Bax/Bcl-2 ratio in comparison with that observed in the SQUU-B cells treated with CMA alone. These findings suggest that CMA could have an anti-tumor effect on OSCCs. In addition, combination of CMA with other agents, such as SAHA, could help improve the pro-apoptotic effects of CMA even in CMA-resistant OSCC cells.
authors.affiliation: Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Kiyoshima
authors.forename: Hisato
authors.initials: H
authors.lastname: Yoshida
authors.forename: Hiroko
authors.initials: H
authors.lastname: Wada
authors.forename: Kengo
authors.initials: K
authors.lastname: Nagata
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Makiko
authors.initials: M
authors.lastname: Kihara
authors.forename: Kana
authors.initials: K
authors.lastname: Hasegawa
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Someya
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Sakai
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D022162:Cytoplasmic Vesicles / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D018942:Macrolides / Q000494:pharmacology*; D009062:Mouth Neoplasms / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D018942:Macrolides; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C036978:concanamycin A; D048051:p38 Mitogen-Activated Protein Kinases; D025262:Vacuolar Proton-Translocating ATPases