Targeting the intrinsic inflammatory pathway: Honokiol exerts proapoptotic effects through STAT3 inhibition in transformed barrett's cells

Chunhua Yu, Qiuyang Zhang, Hui Ying Zhang, Xi Zhang, Xiaofang Huo, Edaire Cheng, David H. Wang, Jack L. Arbiser, Stuart Jon Spechler, Rhonda F. Souza

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

One way to link chronic inflammation with cancer is through the intrinsic inflammatory pathway, in which genetic alterations that induce malignant transformation also produce a cancer-promoting, inflammatory microenvironment. Signal transducer and activator of transcription 3 (STAT3) contributes to the intrinsic inflammatory pathway in Barrett's esophagus. In human tumors, honokiol (a polyphenol in herbal teas) has growthinhibitory and proapoptotic effects associated with suppressed activation of STAT3. We used human Barrett's epithelial and esophageal adenocarcinoma cell lines to determine effects of honokiol on cell number, necrosis, apoptosis, and anchorage-independent growth and to explore STAT3's role in those effects. We determined Ras activity and expression of phosphorylated ERK1/2, phosphorylated Akt, and phosphorylated STAT3 in the presence or absence of honokiol. Cells were infected with constitutively active Stat3-C to assess effects of honokiol-induced STAT3 inhibition on apoptosis. Honokiol decreased cell number and increased necrosis and apoptosis in transformed Barrett's cells, but not in nontransformed cells. In adenocarcinoma cells, honokiol also increased necrosis and apoptosis and decreased anchorage-independent growth. Within 30 min of honokiol treatment, transformed Barrett's cells decreased expression of phosphorylated STAT3; decreases in Ras activity and phosphorylated ERK1/2 expression were detected at 24 h. Infection with Stat3-C significantly reduced apoptosis after honokiol treatment. Honokiol causes necrosis and apoptosis in transformed Barrett's and esophageal adenocarcinoma cells, but not in nontransformed Barrett's cells, and the proapoptotic effects of honokiol are mediated by its inhibition of STAT3 signaling. These findings suggest a potential role for targeting the intrinsic inflammatory pathways as a therapeutic strategy to prevent Barrett's carcinogenesis.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume303
Issue number5
DOIs
StatePublished - Sep 1 2012

Fingerprint

STAT3 Transcription Factor
Apoptosis
Necrosis
Adenocarcinoma
Cell Count
honokiol
Neoplasms
Barrett Esophagus
Polyphenols
Growth
Carcinogenesis
Inflammation
Cell Line

Keywords

  • Akt
  • Barrett's esophagus
  • Esophageal adenocarcinoma
  • Ras
  • Stat3-C

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Cite this

@article{29e5792752814f98867acea9e9a26f88,
title = "Targeting the intrinsic inflammatory pathway: Honokiol exerts proapoptotic effects through STAT3 inhibition in transformed barrett's cells",
abstract = "One way to link chronic inflammation with cancer is through the intrinsic inflammatory pathway, in which genetic alterations that induce malignant transformation also produce a cancer-promoting, inflammatory microenvironment. Signal transducer and activator of transcription 3 (STAT3) contributes to the intrinsic inflammatory pathway in Barrett's esophagus. In human tumors, honokiol (a polyphenol in herbal teas) has growthinhibitory and proapoptotic effects associated with suppressed activation of STAT3. We used human Barrett's epithelial and esophageal adenocarcinoma cell lines to determine effects of honokiol on cell number, necrosis, apoptosis, and anchorage-independent growth and to explore STAT3's role in those effects. We determined Ras activity and expression of phosphorylated ERK1/2, phosphorylated Akt, and phosphorylated STAT3 in the presence or absence of honokiol. Cells were infected with constitutively active Stat3-C to assess effects of honokiol-induced STAT3 inhibition on apoptosis. Honokiol decreased cell number and increased necrosis and apoptosis in transformed Barrett's cells, but not in nontransformed cells. In adenocarcinoma cells, honokiol also increased necrosis and apoptosis and decreased anchorage-independent growth. Within 30 min of honokiol treatment, transformed Barrett's cells decreased expression of phosphorylated STAT3; decreases in Ras activity and phosphorylated ERK1/2 expression were detected at 24 h. Infection with Stat3-C significantly reduced apoptosis after honokiol treatment. Honokiol causes necrosis and apoptosis in transformed Barrett's and esophageal adenocarcinoma cells, but not in nontransformed Barrett's cells, and the proapoptotic effects of honokiol are mediated by its inhibition of STAT3 signaling. These findings suggest a potential role for targeting the intrinsic inflammatory pathways as a therapeutic strategy to prevent Barrett's carcinogenesis.",
keywords = "Akt, Barrett's esophagus, Esophageal adenocarcinoma, Ras, Stat3-C",
author = "Chunhua Yu and Qiuyang Zhang and Zhang, {Hui Ying} and Xi Zhang and Xiaofang Huo and Edaire Cheng and Wang, {David H.} and Arbiser, {Jack L.} and Spechler, {Stuart Jon} and Souza, {Rhonda F.}",
year = "2012",
month = "9",
day = "1",
doi = "10.1152/ajpgi.00033.2012",
language = "English (US)",
volume = "303",
journal = "American Journal of Physiology - Heart and Circulatory Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "5",

}

TY - JOUR

T1 - Targeting the intrinsic inflammatory pathway

T2 - Honokiol exerts proapoptotic effects through STAT3 inhibition in transformed barrett's cells

AU - Yu, Chunhua

AU - Zhang, Qiuyang

AU - Zhang, Hui Ying

AU - Zhang, Xi

AU - Huo, Xiaofang

AU - Cheng, Edaire

AU - Wang, David H.

AU - Arbiser, Jack L.

AU - Spechler, Stuart Jon

AU - Souza, Rhonda F.

PY - 2012/9/1

Y1 - 2012/9/1

N2 - One way to link chronic inflammation with cancer is through the intrinsic inflammatory pathway, in which genetic alterations that induce malignant transformation also produce a cancer-promoting, inflammatory microenvironment. Signal transducer and activator of transcription 3 (STAT3) contributes to the intrinsic inflammatory pathway in Barrett's esophagus. In human tumors, honokiol (a polyphenol in herbal teas) has growthinhibitory and proapoptotic effects associated with suppressed activation of STAT3. We used human Barrett's epithelial and esophageal adenocarcinoma cell lines to determine effects of honokiol on cell number, necrosis, apoptosis, and anchorage-independent growth and to explore STAT3's role in those effects. We determined Ras activity and expression of phosphorylated ERK1/2, phosphorylated Akt, and phosphorylated STAT3 in the presence or absence of honokiol. Cells were infected with constitutively active Stat3-C to assess effects of honokiol-induced STAT3 inhibition on apoptosis. Honokiol decreased cell number and increased necrosis and apoptosis in transformed Barrett's cells, but not in nontransformed cells. In adenocarcinoma cells, honokiol also increased necrosis and apoptosis and decreased anchorage-independent growth. Within 30 min of honokiol treatment, transformed Barrett's cells decreased expression of phosphorylated STAT3; decreases in Ras activity and phosphorylated ERK1/2 expression were detected at 24 h. Infection with Stat3-C significantly reduced apoptosis after honokiol treatment. Honokiol causes necrosis and apoptosis in transformed Barrett's and esophageal adenocarcinoma cells, but not in nontransformed Barrett's cells, and the proapoptotic effects of honokiol are mediated by its inhibition of STAT3 signaling. These findings suggest a potential role for targeting the intrinsic inflammatory pathways as a therapeutic strategy to prevent Barrett's carcinogenesis.

AB - One way to link chronic inflammation with cancer is through the intrinsic inflammatory pathway, in which genetic alterations that induce malignant transformation also produce a cancer-promoting, inflammatory microenvironment. Signal transducer and activator of transcription 3 (STAT3) contributes to the intrinsic inflammatory pathway in Barrett's esophagus. In human tumors, honokiol (a polyphenol in herbal teas) has growthinhibitory and proapoptotic effects associated with suppressed activation of STAT3. We used human Barrett's epithelial and esophageal adenocarcinoma cell lines to determine effects of honokiol on cell number, necrosis, apoptosis, and anchorage-independent growth and to explore STAT3's role in those effects. We determined Ras activity and expression of phosphorylated ERK1/2, phosphorylated Akt, and phosphorylated STAT3 in the presence or absence of honokiol. Cells were infected with constitutively active Stat3-C to assess effects of honokiol-induced STAT3 inhibition on apoptosis. Honokiol decreased cell number and increased necrosis and apoptosis in transformed Barrett's cells, but not in nontransformed cells. In adenocarcinoma cells, honokiol also increased necrosis and apoptosis and decreased anchorage-independent growth. Within 30 min of honokiol treatment, transformed Barrett's cells decreased expression of phosphorylated STAT3; decreases in Ras activity and phosphorylated ERK1/2 expression were detected at 24 h. Infection with Stat3-C significantly reduced apoptosis after honokiol treatment. Honokiol causes necrosis and apoptosis in transformed Barrett's and esophageal adenocarcinoma cells, but not in nontransformed Barrett's cells, and the proapoptotic effects of honokiol are mediated by its inhibition of STAT3 signaling. These findings suggest a potential role for targeting the intrinsic inflammatory pathways as a therapeutic strategy to prevent Barrett's carcinogenesis.

KW - Akt

KW - Barrett's esophagus

KW - Esophageal adenocarcinoma

KW - Ras

KW - Stat3-C

UR - http://www.scopus.com/inward/record.url?scp=84865765186&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84865765186&partnerID=8YFLogxK

U2 - 10.1152/ajpgi.00033.2012

DO - 10.1152/ajpgi.00033.2012

M3 - Article

C2 - 22744336

AN - SCOPUS:84865765186

VL - 303

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 5

ER -