Journal
CANCER SCIENCE
Volume 109, Issue 11, Pages 3611-3622Publisher
WILEY
DOI: 10.1111/cas.13788
Keywords
glycogen synthase kinase-3; nuclear factor-kappa B; protein kinase C; resibufogenin; transforming growth factor-beta-activated kinase 1
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Funding
- CAMS Major Collaborative Innovation Project [2016-12M-1-011]
- National Natural Science Foundation of China [81473248, 81771520, 81773782]
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Resibufogenin (RB), one of the major active compounds of the traditional Chinese medicine Chansu, has received considerable attention for its potency in cancer therapy. However, the anticancer effects and the underlying mechanisms of RB on pancreatic cancer remain elusive. Here, we found that RB inhibited the viability and induces caspase-dependent apoptosis in human pancreatic cancer cells Panc-1 and Aspc. Resibufogenin-induced apoptosis was through inhibition of constitutive nuclear factor-kappa B (NF-kappa B) activity and its target genes' expression, which was caused by downregulation of transforming growth factor-beta-activated kinase 1 (TAK1) levels and suppression of I kappa B kinase activity in Panc-1 and Aspc cells. This induction of TAK1-mediated NF-kappa B inactivation by RB was associated with increased glycogen synthase kinase-3 (GSK-3) phosphorylation and subsequent suppression of its activity. Moreover, RB-induced GSK-3 phosphorylation/inactivation acted through activation of protein kinase C but not Akt. Finally, RB suppressed human pancreatic tumor xenograft growth in athymic nude mice. Thus, our findings reveal a novel mechanism by which RB suppresses TAK1-mediated NF-kappa B activity through protein kinase C-dependent inhibition of GSK-3. Our findings provide a rationale for the potential application of RB in pancreatic cancer therapy.
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