Chemoresistance to concanamycin A1 in human oral squamous cell carcinoma is attenuated by an HDAC inhibitor partly via suppression of Bcl-2 expression

Tamotsu Kiyoshima, Hisato Yoshida, Hiroko Wada, Kengo Nagata, Hiroaki Fujiwara, Makiko Kihara, Kana Hasegawa, Hirotaka Someya, Hidetaka Sakai

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish
Article numbere80998
JournalPloS one
Volume8
Issue number11
DOIs
Publication statusPublished - Nov 20 2013

Fingerprint

Histone Deacetylase Inhibitors
squamous cell carcinoma
B-lymphocytes
Squamous Cell Carcinoma
mouth
B-Lymphocytes
Cells
H-transporting ATP synthase
hydroxamic acids
Adenosine Triphosphatases
Tumors
neoplasms
apoptosis
Apoptosis
acidification
Acidification
Neoplasms
cell lines
cells
Cell Line

All Science Journal Classification (ASJC) codes

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Chemoresistance to concanamycin A1 in human oral squamous cell carcinoma is attenuated by an HDAC inhibitor partly via suppression of Bcl-2 expression. / Kiyoshima, Tamotsu; Yoshida, Hisato; Wada, Hiroko; Nagata, Kengo; Fujiwara, Hiroaki; Kihara, Makiko; Hasegawa, Kana; Someya, Hirotaka; Sakai, Hidetaka.

In: PloS one, Vol. 8, No. 11, e80998, 20.11.2013.

Research output: Contribution to journalArticle

@article{6589ab934205474582a983f15c51c827,
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.",
author = "Tamotsu Kiyoshima and Hisato Yoshida and Hiroko Wada and Kengo Nagata and Hiroaki Fujiwara and Makiko Kihara and Kana Hasegawa and Hirotaka Someya and Hidetaka Sakai",
year = "2013",
month = "11",
day = "20",
doi = "10.1371/journal.pone.0080998",
language = "English",
volume = "8",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "11",

}

TY - JOUR

T1 - Chemoresistance to concanamycin A1 in human oral squamous cell carcinoma is attenuated by an HDAC inhibitor partly via suppression of Bcl-2 expression

AU - Kiyoshima, Tamotsu

AU - Yoshida, Hisato

AU - Wada, Hiroko

AU - Nagata, Kengo

AU - Fujiwara, Hiroaki

AU - Kihara, Makiko

AU - Hasegawa, Kana

AU - Someya, Hirotaka

AU - Sakai, Hidetaka

PY - 2013/11/20

Y1 - 2013/11/20

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84894281739&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84894281739&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0080998

DO - 10.1371/journal.pone.0080998

M3 - Article

VL - 8

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 11

M1 - e80998

ER -