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 growth-inhibitory 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.
authors: Department of Medicine, Veterans Affairs North Texas Health Care System and University of Texas Southwestern Medical Center, Dallas, USA.
authors: Chunhua
authors: C
authors: Yu
authors: Qiuyang
authors: Q
authors: Zhang
authors: Hui Ying
authors: HY
authors: Zhang
authors: Xi
authors: X
authors: Zhang
authors: Xiaofang
authors: X
authors: Huo
authors: Edaire
authors: E
authors: Cheng
authors: David H
authors: DH
authors: Wang
authors: Jack L
authors: JL
authors: Arbiser
authors: Stuart Jon
authors: SJ
authors: Spechler
authors: Rhonda F
authors: RF
authors: Souza
mesh_terms: D000230:Adenocarcinoma / Q000517:prevention & control; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001471:Barrett Esophagus / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D001713:Biphenyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000517:prevention & control; D006801:Humans; D017705:Lignans / Q000494:pharmacology* / Q000627:therapeutic use; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001713:Biphenyl Compounds; D017705:Lignans; D050796:STAT3 Transcription Factor; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols