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

Department of Medicine, Veterans Affairs North Texas Health Care System and University of Texas Southwestern Medical Center, Dallas, USA.
AJP Gastrointestinal and Liver Physiology (Impact Factor: 3.8). 06/2012; 303(5):G561-9. DOI: 10.1152/ajpgi.00033.2012
Source: PubMed


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.

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    • "As GRP78 has a key role in sensing ER stress and subsequent homeostatic responses, agents that interfere or modulate this activity may have therapeutic potential. Although EGCG (Nam et al, 2001) and HNK (Yu et al, 2012) may have other biological properties, studies showing that the AB5 subtilase toxin, which cleaves GRP78 specifically, synergistically enhances the activity of ER stress inducers on melanoma cells (Martin et al, 2010) support the idea that chemical inhibitors of GRP78 may be effective as chemotherapeutic drugs. Nevertheless, although EGCG induces cell death and can overcome resistance to chemotherapeutic drugs (Ermakova et al, 2006; Virrey et al, 2008), on the basis of the present studies it did not have useful properties in combination with agents that induce ER stress. "
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