β‐caryophyllene oxide inhibits constitutive and inducible STAT3 signaling pathway through induction of the SHP‐1 protein tyrosine phosphatase

Abstract

Constitutive activation of STAT3 is frequently observed and closely linked with proliferation, survival, invasion, metastasis and angiogenesis in tumor cells. In the present study, we investigated whether β‐caryophyllene oxide (CPO), a sesquiterpene isolated primarily from the essential oils of medicinal plants such as guava (Psidium guajava), and oregano (Origanum vulgare L.), can mediate its effect through interference with the STAT3 activation pathway in cancer cells. The effect of CPO 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 tumor cell lines. We found that CPO suppressed constitutive STAT3 activation in multiple myeloma (MM), breast and prostate cancer cell lines, with a significant dose‐ and time‐dependent effects observed in MM cells. The suppression was mediated through the inhibition of activation of upstream kinases c‐Src and JAK1/2. Also, vanadate treatment reversed CPO‐induced down‐regulation of STAT3, suggesting the involvement of a tyrosine phosphatase. Indeed, we found that CPO induced the expression of tyrosine phosphatase SHP‐1 that correlated with the down‐regulation of constitutive STAT3 activation. Interestingly, deletion of SHP‐1 gene by siRNA abolished the ability of CPO to inhibit STAT3 activation. The inhibition of STAT3 activation by CPO inhibited proliferation, induced apoptosis and abrogated the invasive potential of tumor cells. Our results suggest for the first time that CPO is a novel blocker of STAT3 signaling cascade and thus has an enormous potential for the treatment of various cancers harboring constitutively activated STAT3. © 2013 Wiley Periodicals, Inc.

Spices for Prevention and Treatment of Cancers

“…For instance, β-caryophyllene oxide, a sesquiterpene isolated from the essential oils of medicinal plants including oregano, showed an anticancer effect through blocking the STAT3 activation pathway in cancer cells [246]. Moreover, carvacrol induced apoptosis via the mitochondrial apoptotic pathway and the MAPK and PI3K/Akt signaling pathways in colon cancer cells [247].…”

Phytopharmacological overview of Psidium guajava Linn.

“…The ability of the meroterpene-enriched fraction to reduce tumor growth and stimulate uterus proliferation, suggest that these compounds may act as Selective Estrogen Receptors Modulators. 97 Kim et al 98 also isolated β-caryophyllene oxide from the essential oils of P. guajava and O. vulgare. β-caryophyllene oxide suppressed constitutive STAT3 activation in multiple myeloma, prostate cancer and breast cancer cell lines.…”

Anti‐inflammatory activity of β‐caryophyllene combined with docosahexaenoic acid in a model of sepsis induced by Staphylococcus aureus in mice

“…β ‐Caryophyllene still inhibits the PI3K/AKT/mTOR/S6K1 pathway, suppressing the expression of phospho‐AKT (Ser473), in a concentration‐dependent manner, in PC‐3 and MCF‐7 cancer cells, and was capable of blocking the IL‐6‐induced activation of STAT‐3 and the upstream elements of the STAT3 pathway (Src, JAK1, and JAK2) in time‐ and dose‐dependent manners, by the expression of tyrosine phosphatase SHP‐1. This indicates that BCP could interfere with TORC2 (the mTOR‐rictor complex that phosphorylates AKT at Ser473) . BCP pretreatment notably produced neuroprotective effects with the phosphorylation of Akt in Ser473.…”