Honokiol inhibits signal transducer and activator of transcription‐3 signaling, proliferation, and survival of hepatocellular carcinoma cells via the protein tyrosine phosphatase SHP‐1

Abstract

The activation of signal transducers and activators of transcription 3 (STAT3) has been closely linked with the proliferation, survival, invasion, and angiogenesis of hepatocellular carcinoma (HCC) and represents an attractive target for therapy. In the present report, we investigated whether honokiol mediates its effect through interference with the STAT3 activation pathway. The effect of honokiol on STAT3 activation, associated protein kinases, and phosphatase, STAT3-regulated gene products and apoptosis was investigated using both functional proteomics tumor pathway technology platform and different HCC cell lines. We found that honokiol inhibited both constitutive and inducible STAT3 activation in a dose- and time-dependent manner in HCC cells. The suppression was mediated through the inhibition of activation of upstream kinases c-Src, Janus-activated kinase 1, and Janus-activated kinase 2. Vanadate treatment reversed honokiol-induced down-regulation of STAT3, suggesting the involvement of a tyrosine phosphatase. Indeed, we found that honokiol induced the expression of tyrosine phosphatase SHP-1 that correlated with the down-regulation of constitutive STAT3 activation. Moreover, deletion of SHP-1 gene by siRNA abolished the ability of honokiol to inhibit STAT3 activation. The inhibition of STAT3 activation by honokiol led to the suppression of various gene products involved in proliferation, survival, and angiogenesis. Finally, honokiol inhibited proliferation and significantly potentiated the apoptotic effects of paclitaxel and doxorubicin in HCC cells. Overall, the results suggest that honokiol is a novel blocker of STAT3 activation and may have a great potential for the treatment of HCC and other cancers.

Targeting the STAT3 signaling pathway in cancer: Role of synthetic and natural inhibitors

“…The ability of honokiol to modulate constitutive STAT3 activation in HCC cells was investigated by Rajendran et al [268]. HepG2 cells were incubated with different concentrations of honokiol for 6 h, and the phosphorylation of STAT3 was examined by Western blot.…”

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

“…Natural agents, peptides, platinum compounds and other small molecules have been used to inhibit STAT3 activity in various tumor models including HCC [258]. Our group has identified number of STAT3 inhibitors including diosgenin, β-escin, γ-tocotrienol, butein, honokiol, and celastrol that can suppress growth and induce apoptosis in diverse HCC cell lines [259][260][261][262][263][264]. In addition, Chen and coworkers recently reported that a novel obatoclax derivative, SC-2001, can induce apoptosis in hepatocellular carcinoma cells through SHP-1-dependent STAT3 inactivation [265].…”

Honokiol Inhibits Constitutive and Inducible STAT3 Signaling via PU.1-Induced SHP1 Expression in Acute Myeloid Leukemia Cells

“…HNK has been reported to regulate a series of signal pathway including PI3K/mTOR pathway (Crane et al 2009), p38 MAP kinase pathway (Deng et al 2008), and STAT signaling (Rajendran et al 2012) in various cancer cells. Our previous data also indicated that HNK induced apoptosis and cell growth arrest in leukemic cells by inhibiting histone deacetylases (HDAC) activity (Li et al 2015).…”

“…Further more, HNK inhibited cell growth and induced apoptosis via decreasing expression of phosphorylated STAT3 and phosphorylated ERK1/2 in human Barrett's epithelial and esophageal adenocarcinoma cells (Yu et al 2012). HNK inhibits STAT3 signaling via increasing SHP1 expression in hepatocellular carcinoma cells (Rajendran et al 2012). However, the mechanism by which HNK induces SHP1 expression in AML cells remains unclear.…”