Journal
PHYTOMEDICINE
Volume 55, Issue -, Pages 282-292Publisher
ELSEVIER GMBH
DOI: 10.1016/j.phymed.2018.06.038
Keywords
Arctiin; STAT3; PTP epsilon; Apoptosis; MM
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Funding
- National Research Foundation of Korea (NRF) - Korean government (MSIP) [NRF-2017M3A9E4065333, 2017R1A6A3A11031224, 2018R1D 1A1B07042969]
- National Research Foundation of Korea [2017R1A6A3A11031224] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Background: Arctiin is a main component from the fruits of Arctium lappa L., that can be prescribed for cold or flu in East Asian countries; it has also been found to exert chemopreventive actions against various tumor cells. Hypothesis: In view of this evidence, we examined arctiin for its ability to trigger apoptosis and inhibit the activation of signal transducer and activator of transcription 3 (STAT3) in human multiple myeloma (MM) cells. Methods: We evaluated the effect of arctiin on STAT3 signaling cascades and its regulated functional responses in MM cells. Results: Arctiin effectively blocked the constitutive activation of STAT3 phosphorylation in the residue of tyrosine 705. Arctiin also abrogated the constitutive activation of Src phosphorylation and Janus-activated kinases (JAKs) 1/2. Furthermore, it was found that arctiin treatment clearly enhanced the mRNA and protein levels of protein tyrosine phosphatase epsilon (PTP epsilon), and the silencing of PTPe caused a reversal of the arctiin-induced PTPe expression and the blockadge of STAT3 phosphorylation. Interestingly, arctiin could not repress IL-6-induced STAT3 activation in serum-starved U266 cells and when arctiin was incubated with a complete culture medium in RPMI 8226 and MM.1S cells. Arctiin suppressed cell proliferation, accumulated cells in the G2/M cell-cycle phase, and induced apoptosis within U266 cells, although the knockdown of PTPe prevented PARP cleavage and caspase-3 activation induced by the arctiin. In addition, arctiin exerted cytotoxicity in MM cells, but did not do so in peripheral blood mononuclear cells. Arctiin down-modulated diverse oncogenic gene products regulated by STAT3, although the induction of apoptosis by arctiin was abrogated upon transfection with pMXs-STAT3C in mouse embryonic fibroblast (MEF) cells. Arctiin also potentiated bortezomib-induced antitumor effects in U266 cells. Conclusion: On the whole, our results indicate that arctiin is a potentially new inhibitor of constitutive STAT3 activation through the induction of PTPe in MM, cells and therefore has great value in treating various tumors sheltering constitutively activated STAT3.
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