Patulin induces colorectal cancer cells apoptosis through EGR-1 dependent ATF3 up-regulation.
Patulin is a fungal mycotoxin of Aspergilus and Penicillium that is commonly found in rotting fruits and exerts its potential toxic effect mainly by reactive oxygen species (ROS) generation. However, the effect of patulin on cancer cells as well as its intracellular mechanism has been controversial and not clearly defined yet. In this study, patulin was found to induce G1/S accumulation and cell growth arrest accompanied by caspase-3 activation, PARP cleavage and ATF3 expression in human colon cancer cell line HCT116. Ser/Thr phosphorylation of a transcription factor, EGR-1, was increased while its expression did not change upon patulin treatment to the cells. Knockdown of ATF3 and EGR-1 using their respective siRNAs showed EGR-1 dependent ATF3 expression. Moreover, treatment of the cells with antioxidants N-acetylcysteine (NAC) and glutathione (GSH) revealed that patulin induced ATF3 expression and apoptosis were dependent on ROS generation. ATF3 expression was also increased by patulin in other colorectal cancer cell types, Caco2 and SW620. Collectively, our data present a new anti-cancer molecular mechanism of patulin, suggesting EGR-1 and ATF3 as critical targets for the development of anti-cancer chemotherapeutics. In this regard, patulin could be a candidate for the treatment of colorectal cancers.
Korea Research Institute of Bioscience and Biotechnology (KRIBB), 685-2 Ochang-eup, Cheongwon-gun 363-883, Republic of Korea.
Osong
O
Kwon
Nak Kyun
NK
Soung
N R
NR
Thimmegowda
Sook Jung
SJ
Jeong
Jae Hyuk
JH
Jang
Dong-Oh
DO
Moon
Jong Kyeong
JK
Chung
Kyung Sang
KS
Lee
Yong Tae
YT
Kwon
Raymond Leo
RL
Erikson
Jong Seog
JS
Ahn
Bo Yeon
BY
Kim
D000111:Acetylcysteine / Q000494:pharmacology; D051700:Activating Transcription Factor 3 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics*; D018938:Caco-2 Cells; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D005978:Glutathione / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D009183:Mycotoxins / Q000494:pharmacology; D010365:Patulin / Q000494:pharmacology*; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D000975:Antioxidants; D009183:Mycotoxins; D017382:Reactive Oxygen Species; D010365:Patulin; D011065:Poly(ADP-ribose) Polymerases; D017526:Receptor, IGF Type 1; D053148:Caspase 3; D005978:Glutathione; D000111:Acetylcysteine