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2'-hydroxycinnamaldehyde inhibits cancer cell proliferation and tumor growth by targeting the pyruvate kinase M2.

Abstract
It is reported that 2'-hydroxycinnamaldehyde (HCA), isolated from cinnamon, has anti-tumor effects through the modulation of multi-target molecules. In this study, we identified pyruvate kinase M2 (PKM2) as a direct target of HCA by use of biochemical methods including affinity chromatography, drug affinity responsive target stability, and cellular thermal shift assay. PKM2 is up-regulated in multiple cancer types and is considered as a potential target for cancer therapy. HCA binds directly to PKM2 and selectively decreases the phosphorylation of PKM2 at Tyr105, indicating a potential anti-proliferative effect on prostate cancer cells. As a PKM2 activator, HCA increases pyruvate kinase activity by promoting the tetrameric state of PKM2. However, HCA suppresses protein kinase activity of PKM2 by decreasing the phosphorylation at Tyr105. Moreover, this leads to a decrease of PKM2-mediated STAT3 phosphorylation at Tyr705 and a down-regulation of target genes, including MEK5 and cyclin D1. Furthermore, HCA suppresses tumor growth and the release of tumor extracellular vesicles in vivo by inhibiting the phosphorylation of PKM2. Collectively, our results suggest that HCA may be a potential anticancer agent targeting PKM2 in cancer progression.
AuthorsYae Jin Yoon, Young-Hwan Kim, Yena Jin, Seung-Wook Chi, Jeong Hee Moon, Dong Cho Han, Byoung-Mog Kwon
JournalCancer letters (Cancer Lett) Vol. 434 Pg. 42-55 (10 10 2018) ISSN: 1872-7980 [Electronic] Ireland
PMID30009856 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2018 Elsevier B.V. All rights reserved.
Chemical References
  • Cinnamates
  • STAT3 Transcription Factor
  • p-hydroxycinnamaldehyde
  • Pyruvate Kinase
Topics
  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Cinnamates (pharmacology)
  • HCT116 Cells
  • Humans
  • Male
  • Mice, Nude
  • PC-3 Cells
  • Phosphorylation (drug effects)
  • Prostatic Neoplasms (drug therapy, metabolism, pathology)
  • Protein Multimerization (drug effects)
  • Pyruvate Kinase (antagonists & inhibitors, chemistry, metabolism)
  • STAT3 Transcription Factor (metabolism)
  • Tumor Burden (drug effects)
  • Xenograft Model Antitumor Assays

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