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Cited by 155Autophagy in Disease and TherapyProtease and Inhibitor MechanismsCell death mechanisms and regulation

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Cathepsin L mediates resveratrol-induced autophagy and apoptotic cell death in cervical cancer cells

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Hsu, Keng-Fu, Wu, Chao-Liang, Huang, Soon-Cen, Wu, Ching-Ming, Hsiao, Jenn-Ren, Yo, Yi-Te, Chen, Yu-Hung, Shiau, Ai-Li, Chou, Cheng-Yang·2009·Autophagy
DOI 10.4161/auto.5.4.7666
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Abstract

Cathepsins have long been considered as housekeeping molecules. However, specific functions have also been attributed to each of these lysosomal proteases. Squamous cell carcinoma antigen (SCCA) 1, widely expressed in various uterine cervical cells, is an endogenous cathepsin (cat) L inhibitor. In this study, we investigated whether the cat L-SCCA 1 lysosomal pathway and autophagy were involved in resveratrol (RSV)-induced cytotoxicity in cervical cancer cells. RSV induced GFP-LC3 aggregation as well as increased the presence of LC3-II and autophagosomes as was revealed by electron microscopy in cervical cancer cells. Prolonged treatment of RSV induced cytosolic translocation of cytochrome c, caspase 3 activation and apoptotic cell death. This apoptotic effect was abrogated by trans-epoxysuccinyl-L-leucylamido-(4-guanidino)butane, an inhibitor of cat B and L, but not by pepstatin A, an inhibitor of cat D. As cervical cancer cells express little cat B, we further studied the role of cat L. RSV induced dissipation of the lysosomal membrane permeability (LMP), leakage and increased cytosolic expression and activity of cat L. Inhibition of cat L by small interference RNA (siRNA) protected cells from RSV-induced cytotoxicity. In contrast, inhibition of SCCA 1 by siRNA promoted RSV-induced cytotoxicity. Inhibition of autophagic response by wortmannin (WT) or asparagine (ASP) resulted in decreased early LC3-II formation, reduced LMP, and abolishment of the increase in RSV-induced cell death. In conclusion, we have identified a new cytotoxic mechanism in which the lysosomal enzyme cat L acts as a death signal integrator in cervical cancer cells. Furthermore, SCCA 1 may play an antiapoptotic role through anti-cat L activity.

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Authors
Hsu, K.-F., Wu, C.-L., Huang, S.-C., Wu, C.-M., Hsiao, J.-R., Yo, Y.-T., Chen, Y.-H., Shiau, A.-L., & Chou, C.-Y.
Affiliations
  • National Cheng Kung University (TW)
  • Chi Mei Medical Center (TW)
  • National Cheng Kung University Hospital (TW)
Corresponding author
  • Shiau, Ai-Li
  • Chou, Cheng-Yang
ORCID
Venue
Autophagy
Publisher
Informa UK Limited
Published
2009-05-16
Volume
5
Issue
4
Pages
451-460
ISSN
  • 1554-8627 (ISSN-L)
  • 1554-8635
DOI
10.4161/auto.5.4.7666
OpenAlex
W2113492659
Cited by
155
References
0
Citations by year
2026: 3 · 2025: 6 · 2024: 6 · 2023: 6 · 2022: 11 · 2021: 5 · 2020: 15 · 2019: 7 · 2018: 14 · 2017: 11 · 2016: 9 · 2015: 11 · 2014: 11 · 2013: 9 · 2012: 12
FWCI
6.94
Type
journal article
Language
en
Open access
Locations
  • Autophagy (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Science Council
  • National Cheng Kung University
  • National Institute for Basic Biology
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
cathepsin L, resveratrol, cervical cancer, apoptosis, SCCA1, lysosomal membrane permeability, LC3-II, cytochrome c release, caspase-3 activation, lysosomal proteases, wortmannin, L-asparaginase, siRNA knockdown
MeSH terms
Resveratrol, Autophagy, Cathepsins, Uterine Cervical Neoplasms, Cysteine Endopeptidases, Cytosol, Enzyme Activation, Extracellular Space, Female, Humans, Intracellular Membranes, Iron, Lysosomes, Models, Biological, Permeability, Stilbenes, Apoptosis, Protein Transport, Cytochromes c, Cell Line, Tumor, Cell Proliferation, Caspase 3, Cathepsin L

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