Trichodermin induces c-Jun N-terminal kinase-dependent apoptosis caused by mitotic arrest and DNA damage in human p53-mutated pancreatic cancer cells and xenografts

Ming Hsien Chien, Tzong Huei Lee, Wei Jiunn Lee, Yen Hsiu Yeh, Tsai Kun Li, Po Chuan Wang, Jih Jung Chen, Jyh Ming Chow, Yung Wei Lin, Michael Hsiao, Shih Wei Wang, Kuo Tai Hua

研究成果: 雜誌貢獻文章

4 引文 (Scopus)

摘要

Pancreatic cancer is an aggressive malignancy, which generally responds poorly to chemotherapy. In this study, trichodermin, an endophytic fungal metabolite from Nalanthamala psidii, was identified as a potent and selective antitumor agent in human pancreatic cancer. Trichodermin exhibited antiproliferative effects against pancreatic cancer cells, especially p53-mutated cells (MIA PaCa-2 and BxPC-3) rather than normal pancreatic epithelial cells. We found that trichodermin induced caspase-dependent and mitochondrial intrinsic apoptosis. Trichodermin also increased apoptosis through mitotic arrest by activating Cdc2/cyclin B1 complex activity. Moreover, trichodermin promoted the activation of c-Jun N-terminal kinase (JNK), and inhibition of JNK by its inhibitor, shRNA, or siRNA significantly reversed trichodermin-mediated caspase-dependent apoptosis. Trichodermin triggered DNA damage stress to activate p53 function for executing apoptosis in p53-mutated cells. Importantly, we demonstrated that trichodermin with efficacy similar to gemcitabine, profoundly suppressed tumor growth through inducing intratumoral DNA damage and JNK activation in orthotopic pancreatic cancer model. Based on these findings, trichodermin is a potential therapeutic agent worthy of further development into a clinical trial candidate for treating cancer, especially the mutant p53 pancreatic cancer.
原文英語
頁(從 - 到)249-261
頁數13
期刊Cancer Letters
388
DOIs
出版狀態已發佈 - 三月 1 2017

指紋

Trichodermin
JNK Mitogen-Activated Protein Kinases
Pancreatic Neoplasms
Heterografts
DNA Damage
Apoptosis
gemcitabine
Caspases
Small Interfering RNA
Cyclin B1
Neoplasms
Antineoplastic Agents

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

引用此文

Trichodermin induces c-Jun N-terminal kinase-dependent apoptosis caused by mitotic arrest and DNA damage in human p53-mutated pancreatic cancer cells and xenografts. / Chien, Ming Hsien; Lee, Tzong Huei; Lee, Wei Jiunn; Yeh, Yen Hsiu; Li, Tsai Kun; Wang, Po Chuan; Chen, Jih Jung; Chow, Jyh Ming; Lin, Yung Wei; Hsiao, Michael; Wang, Shih Wei; Hua, Kuo Tai.

於: Cancer Letters, 卷 388, 01.03.2017, p. 249-261.

研究成果: 雜誌貢獻文章

Chien, Ming Hsien ; Lee, Tzong Huei ; Lee, Wei Jiunn ; Yeh, Yen Hsiu ; Li, Tsai Kun ; Wang, Po Chuan ; Chen, Jih Jung ; Chow, Jyh Ming ; Lin, Yung Wei ; Hsiao, Michael ; Wang, Shih Wei ; Hua, Kuo Tai. / Trichodermin induces c-Jun N-terminal kinase-dependent apoptosis caused by mitotic arrest and DNA damage in human p53-mutated pancreatic cancer cells and xenografts. 於: Cancer Letters. 2017 ; 卷 388. 頁 249-261.
@article{bfce128d5fa64989867a3ac033a855f5,
title = "Trichodermin induces c-Jun N-terminal kinase-dependent apoptosis caused by mitotic arrest and DNA damage in human p53-mutated pancreatic cancer cells and xenografts",
abstract = "Pancreatic cancer is an aggressive malignancy, which generally responds poorly to chemotherapy. In this study, trichodermin, an endophytic fungal metabolite from Nalanthamala psidii, was identified as a potent and selective antitumor agent in human pancreatic cancer. Trichodermin exhibited antiproliferative effects against pancreatic cancer cells, especially p53-mutated cells (MIA PaCa-2 and BxPC-3) rather than normal pancreatic epithelial cells. We found that trichodermin induced caspase-dependent and mitochondrial intrinsic apoptosis. Trichodermin also increased apoptosis through mitotic arrest by activating Cdc2/cyclin B1 complex activity. Moreover, trichodermin promoted the activation of c-Jun N-terminal kinase (JNK), and inhibition of JNK by its inhibitor, shRNA, or siRNA significantly reversed trichodermin-mediated caspase-dependent apoptosis. Trichodermin triggered DNA damage stress to activate p53 function for executing apoptosis in p53-mutated cells. Importantly, we demonstrated that trichodermin with efficacy similar to gemcitabine, profoundly suppressed tumor growth through inducing intratumoral DNA damage and JNK activation in orthotopic pancreatic cancer model. Based on these findings, trichodermin is a potential therapeutic agent worthy of further development into a clinical trial candidate for treating cancer, especially the mutant p53 pancreatic cancer.",
keywords = "Apoptosis, c-Jun N-terminal kinase, DNA damage, Mitotic arrest, Pancreatic cancer, Trichodermin",
author = "Chien, {Ming Hsien} and Lee, {Tzong Huei} and Lee, {Wei Jiunn} and Yeh, {Yen Hsiu} and Li, {Tsai Kun} and Wang, {Po Chuan} and Chen, {Jih Jung} and Chow, {Jyh Ming} and Lin, {Yung Wei} and Michael Hsiao and Wang, {Shih Wei} and Hua, {Kuo Tai}",
year = "2017",
month = "3",
day = "1",
doi = "10.1016/j.canlet.2016.12.002",
language = "English",
volume = "388",
pages = "249--261",
journal = "Cancer Letters",
issn = "0304-3835",
publisher = "Elsevier Ireland Ltd",

}

TY - JOUR

T1 - Trichodermin induces c-Jun N-terminal kinase-dependent apoptosis caused by mitotic arrest and DNA damage in human p53-mutated pancreatic cancer cells and xenografts

AU - Chien, Ming Hsien

AU - Lee, Tzong Huei

AU - Lee, Wei Jiunn

AU - Yeh, Yen Hsiu

AU - Li, Tsai Kun

AU - Wang, Po Chuan

AU - Chen, Jih Jung

AU - Chow, Jyh Ming

AU - Lin, Yung Wei

AU - Hsiao, Michael

AU - Wang, Shih Wei

AU - Hua, Kuo Tai

PY - 2017/3/1

Y1 - 2017/3/1

N2 - Pancreatic cancer is an aggressive malignancy, which generally responds poorly to chemotherapy. In this study, trichodermin, an endophytic fungal metabolite from Nalanthamala psidii, was identified as a potent and selective antitumor agent in human pancreatic cancer. Trichodermin exhibited antiproliferative effects against pancreatic cancer cells, especially p53-mutated cells (MIA PaCa-2 and BxPC-3) rather than normal pancreatic epithelial cells. We found that trichodermin induced caspase-dependent and mitochondrial intrinsic apoptosis. Trichodermin also increased apoptosis through mitotic arrest by activating Cdc2/cyclin B1 complex activity. Moreover, trichodermin promoted the activation of c-Jun N-terminal kinase (JNK), and inhibition of JNK by its inhibitor, shRNA, or siRNA significantly reversed trichodermin-mediated caspase-dependent apoptosis. Trichodermin triggered DNA damage stress to activate p53 function for executing apoptosis in p53-mutated cells. Importantly, we demonstrated that trichodermin with efficacy similar to gemcitabine, profoundly suppressed tumor growth through inducing intratumoral DNA damage and JNK activation in orthotopic pancreatic cancer model. Based on these findings, trichodermin is a potential therapeutic agent worthy of further development into a clinical trial candidate for treating cancer, especially the mutant p53 pancreatic cancer.

AB - Pancreatic cancer is an aggressive malignancy, which generally responds poorly to chemotherapy. In this study, trichodermin, an endophytic fungal metabolite from Nalanthamala psidii, was identified as a potent and selective antitumor agent in human pancreatic cancer. Trichodermin exhibited antiproliferative effects against pancreatic cancer cells, especially p53-mutated cells (MIA PaCa-2 and BxPC-3) rather than normal pancreatic epithelial cells. We found that trichodermin induced caspase-dependent and mitochondrial intrinsic apoptosis. Trichodermin also increased apoptosis through mitotic arrest by activating Cdc2/cyclin B1 complex activity. Moreover, trichodermin promoted the activation of c-Jun N-terminal kinase (JNK), and inhibition of JNK by its inhibitor, shRNA, or siRNA significantly reversed trichodermin-mediated caspase-dependent apoptosis. Trichodermin triggered DNA damage stress to activate p53 function for executing apoptosis in p53-mutated cells. Importantly, we demonstrated that trichodermin with efficacy similar to gemcitabine, profoundly suppressed tumor growth through inducing intratumoral DNA damage and JNK activation in orthotopic pancreatic cancer model. Based on these findings, trichodermin is a potential therapeutic agent worthy of further development into a clinical trial candidate for treating cancer, especially the mutant p53 pancreatic cancer.

KW - Apoptosis

KW - c-Jun N-terminal kinase

KW - DNA damage

KW - Mitotic arrest

KW - Pancreatic cancer

KW - Trichodermin

UR - http://www.scopus.com/inward/record.url?scp=85007173843&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85007173843&partnerID=8YFLogxK

U2 - 10.1016/j.canlet.2016.12.002

DO - 10.1016/j.canlet.2016.12.002

M3 - Article

C2 - 27965041

AN - SCOPUS:85007173843

VL - 388

SP - 249

EP - 261

JO - Cancer Letters

JF - Cancer Letters

SN - 0304-3835

ER -