Sulforaphane induces cytotoxicity and lysosome- and mitochondria-dependent cell death in colon cancer cells with deleted p53

Emil Rudolf; Miroslav Cervinka

doi:10.1016/j.tiv.2011.04.019

Sulforaphane induces cytotoxicity and lysosome- and mitochondria-dependent cell death in colon cancer cells with deleted p53

Toxicol In Vitro. 2011 Oct;25(7):1302-9. doi: 10.1016/j.tiv.2011.04.019. Epub 2011 May 1.

Authors

Emil Rudolf¹, Miroslav Cervinka

Affiliation

¹ Department of Medical Biology and Genetics, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Simkova 870, 500 38 Hradec Kralove, Czech Republic. rudolf@lfhk.cuni.cz

PMID: 21557998
DOI: 10.1016/j.tiv.2011.04.019

Abstract

Mechanisms and pathways responsible for cytotoxicity of sulforaphane (SF) in colon cancer cells with deleted p53 were investigated during 48 h of exposure. SF showed dose-dependent cytotoxicity and proapoptotic activity in the present model. In addition, in HCT-116 p53KO cells SF induced DNA damage with the subsequent cellular response and signaling not including p53 and caspase-2 pathways. Conversely, in SF-treated cells JNK was activated which led to an early lysosomal membrane permeabilization, release of cathepsin B and D and activation of Bid by specific cleavage. Concomitantly, the expression of Bax increased in the presence of JNK-mediated Bcl-2 inhibition which was followed by mitochondrial release of cytochrome c and activation of apoptosis. These results suggest that SF may be useful as a chemopreventive agent in colon cancer with inactivated or lost p53.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anticarcinogenic Agents / toxicity*
Cell Proliferation / drug effects
Cell Survival / drug effects
Colonic Neoplasms / genetics
Colonic Neoplasms / metabolism*
Colonic Neoplasms / prevention & control
DNA Damage / drug effects
Gene Deletion
Gene Expression Regulation, Neoplastic / drug effects
HCT116 Cells
Heat-Shock Proteins / genetics
Heat-Shock Proteins / metabolism
Humans
Isothiocyanates
Lysosomes / drug effects
Lysosomes / metabolism*
MAP Kinase Kinase 4 / genetics
MAP Kinase Kinase 4 / metabolism
Mitochondria / drug effects
Mitochondria / metabolism*
Stress, Physiological / drug effects
Sulfoxides
Thiocyanates / toxicity*
Time Factors
Tumor Suppressor Protein p53 / genetics*
Tumor Suppressor Protein p53 / metabolism
bcl-2-Associated X Protein / genetics
bcl-2-Associated X Protein / metabolism

Substances

Anticarcinogenic Agents
BAX protein, human
Heat-Shock Proteins
Isothiocyanates
Sulfoxides
Thiocyanates
Tumor Suppressor Protein p53
bcl-2-Associated X Protein
MAP Kinase Kinase 4
sulforaphane