Celecoxib-induced cytotoxic effect is potentiated by inhibition of autophagy in human urothelial carcinoma cells

Kuo-How Huang; Kuan-Lin Kuo; I-Lin Ho; Hong-Chiang Chang; Yuan-Ting Chuang; Wei-Chou Lin; Ping-Yi Lee; Shih-Chen Chang; Chih-Kang Chiang; Yeong-Shiau Pu; Chien-Tso Chou; Chen-Hsun Hsu; Shing-Hwa Liu

doi:10.1371/journal.pone.0082034

Celecoxib-induced cytotoxic effect is potentiated by inhibition of autophagy in human urothelial carcinoma cells

PLoS One. 2013 Dec 9;8(12):e82034. doi: 10.1371/journal.pone.0082034. eCollection 2013.

Authors

Affiliations

¹ Graduate institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan ; Department of Urology, National Taiwan University Hospital, Taipei, Taiwan.
² Department of Urology, National Taiwan University Hospital, Taipei, Taiwan.
³ Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
⁴ Department of Urology, National Taiwan University Hospital, Taipei, Taiwan ; Department of Chemical Engineering, College of Engineering, National Taiwan University, Taipei, Taiwan.
⁵ Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, Taipei, Taiwan.
⁶ Graduate institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.

Abstract

Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, can elicit anti-tumor effects in various malignancies. Here, we sought to clarify the role of autophagy in celecoxib-induced cytotoxicity in human urothelial carcinoma (UC) cells. The results shows celecoxib induced cellular stress response such as endoplasmic reticulum (ER) stress, phosopho-SAPK/JNK, and phosopho-c-Jun as well as autophagosome formation in UC cells. Inhibition of autophagy by 3-methyladenine (3-MA), bafilomycin A1 or ATG7 knockdown potentiated celecoxib-induced apoptosis. Up-regulation of autophagy by rapamycin or GFP-LC3B-transfection alleviated celecoxib-induced cytotoxicity in UC cells. Taken together, the inhibition of autophagy enhances therapeutic efficacy of celecoxib in UC cells, suggesting a novel therapeutic strategy against UC.

MeSH terms

Adenine / analogs & derivatives
Adenine / pharmacology
Antineoplastic Agents / pharmacology*
Autophagy / drug effects*
Autophagy-Related Protein 7
Carcinoma, Transitional Cell / drug therapy
Carcinoma, Transitional Cell / genetics
Carcinoma, Transitional Cell / metabolism
Carcinoma, Transitional Cell / pathology
Celecoxib
Cell Line, Tumor
Cyclooxygenase 2 Inhibitors / pharmacology*
Endoplasmic Reticulum Stress / drug effects
Gene Expression Regulation, Neoplastic*
Humans
JNK Mitogen-Activated Protein Kinases / genetics
JNK Mitogen-Activated Protein Kinases / metabolism
MAP Kinase Kinase 4 / genetics
MAP Kinase Kinase 4 / metabolism
Macrolides / pharmacology
Phosphoproteins / genetics
Phosphoproteins / metabolism
Pyrazoles / pharmacology*
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Signal Transduction
Sirolimus / pharmacology
Sulfonamides / pharmacology*
Ubiquitin-Activating Enzymes / antagonists & inhibitors
Ubiquitin-Activating Enzymes / genetics
Ubiquitin-Activating Enzymes / metabolism
Urinary Bladder Neoplasms / drug therapy
Urinary Bladder Neoplasms / genetics
Urinary Bladder Neoplasms / metabolism
Urinary Bladder Neoplasms / pathology

Substances

Antineoplastic Agents
Cyclooxygenase 2 Inhibitors
Macrolides
Phosphoproteins
Pyrazoles
RNA, Small Interfering
Sulfonamides
3-methyladenine
bafilomycin A1
JNK Mitogen-Activated Protein Kinases
MAP Kinase Kinase 4
ATG7 protein, human
Autophagy-Related Protein 7
Ubiquitin-Activating Enzymes
Adenine
Celecoxib
Sirolimus

Grants and funding

This work was supported by a grant from Taiwan National Science Council (NSC 98-2314-B-002-056 and 101-2314-B-002-025-). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.