Resveratrol induces cell death in colorectal cancer cells by a novel pathway involving lysosomal cathepsin D

Trincheri, N. F.; Nicotra, G.; Follo, C.; Castino, R.; Isidoro, C.

doi:10.1093/carcin/bgl223

Cited by 122Sirtuins and Resveratrol in MedicineCell death mechanisms and regulationProtease and Inhibitor Mechanisms

Resveratrol induces cell death in colorectal cancer cells by a novel pathway involving lysosomal cathepsin D

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Trincheri, N. F., Nicotra, G., Follo, C., Castino, R., Isidoro, C.·2006·Carcinogenesis

DOI 10.1093/carcin/bgl223

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Abstract

In human colorectal cancer cells, the polyphenol resveratrol (RV) activated the caspase-dependent intrinsic pathway of apoptosis. This effect was not mediated via estrogen receptors. Pepstatin A, an inhibitor of lysosomal cathepsin D (CD), not (2S,3S)-trans-epoxysuccinyl-L-leucylamido-3-methylbutane ethyl ester, an inhibitor of cathepsins B and L, prevented RV cytotoxicity. Similar protection was attained by small interference RNA-mediated knockdown of CD protein expression. RV promoted the accumulation of mature CD, induced lysosome leakage and increased cytosolic immunoreactivity of CD. Inhibition of CD or its post-transcriptional down-regulation precluded Bax oligomerization, permeabilization of mitochondrial membrane, cytosolic translocation of cytochrome c, caspase 3 activation and terminal deoxinucleotidyl transferase-mediated dUTP-biotin nick end labeling positivity occurring in RV-treated cells. The present study identifies the lysosome as a novel target of RV activity and demonstrates a hierarchy of the proteolytic pathways involved in its cytotoxic mechanism in which the lysosomal CD acts upstream of the cytosolic caspase activation. Our data indicate that metabolic, pharmacologic or genetic conditions affecting CD expression and/or activity could reflect on the sensitivity of cancer cells to RV.

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CTSL plays a key role in regulating autophagic adaptation vs. RCD in cells responding to resveratrol.
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Authors: Trincheri, N. F., Nicotra, G., Follo, C., Castino, R., & Isidoro, C.
Affiliations: Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
Corresponding author: Isidoro, C.
ORCID: Follo, C.
Isidoro, C.
Venue: Carcinogenesis
Publisher: Oxford University Press (OUP)
Published: 2006-11-27
Volume: 28
Issue: 5
Pages: 922-931
ISSN: 0143-3334 (ISSN-L)
1460-2180
DOI: 10.1093/carcin/bgl223
OpenAlex: W2116178196
Cited by: 122
References: 51
Citations by year: 2026: 1 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 7 · 2021: 5 · 2020: 6 · 2019: 7 · 2018: 8 · 2017: 7 · 2016: 8 · 2015: 7 · 2014: 5 · 2013: 12 · 2012: 10
FWCI: 2.73
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
Locations: Carcinogenesis (publishedVersion, cc-by)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Keywords: resveratrol, colorectal cancer, cathepsin D, lysosomal cathepsins, apoptosis, caspase-3 activation, Bax oligomerization, mitochondrial membrane permeabilization, cytochrome c release, lysosomal proteolysis, pepstatin A
MeSH terms: Resveratrol, Cathepsin D, Cathepsins, Cell Line, Cysteine Endopeptidases, Cytosol, Dose-Response Relationship, Drug, Humans, Lysosomes, Stilbenes, Time Factors, Colorectal Neoplasms, Cell Death, HT29 Cells, Cytochromes c, Cathepsin L, Caspase Inhibitors

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Resveratrol induces cell death in colorectal cancer cells by a novel pathway involving lysosomal cathepsin D

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