Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume 1853, Issue 1, Pages 157-165Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamcr.2014.10.013
Keywords
Glaucarubinone; PAK1; HIF-1 alpha; beta-Catenin; CRC
Categories
Funding
- National Health and Medical Research Council (NHMRC) of Australia [508908, 1041831]
- Austin Hospital Medical Research Foundation [2-1281]
- Intramural Research Program of the NIH National Cancer Institute Center for Cancer Research [1 ZIA BC011470 02]
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p-21-Activated kinase 1 (PAK1) enhances colorectal cancer (CRC) progression by stimulating Wnt/beta-catenin, ERK and AKT pathways. PAK1 also promotes CRC survival via up-regulation of hypoxia-inducible factor 1 alpha (HIF-1 alpha), a key player in cancer survival. Glaucarubinone, a quassinoid natural product, inhibits pancreatic cancer growth by down-regulation of PAK1. The aim of this study was to investigate the effect of glaucarubinone on CRC growth and metastasis, and the mechanism involved. Cell proliferation was measured in vitro by [H-3]-thymidine incorporation and in vivo by volume of tumor xenografts. Protein concentrations were measured by Western blotting of cell extracts. We report here that glaucarubinone inhibited CRC growth both in vitro and in vivo. The potency of glaucarubinone as an inhibitor of cell proliferation was negatively correlated to PAK1 expression in CRC cells. Glaucarubinone suppressed the expression of HIF-1 alpha and beta-catenin. Knockdown of PAK1 by shRNA enhanced inhibition by glaucarubinone while constitutively active PAK1 blocked the inhibitory effect. Our findings indicate that glaucarubinone inhibited CRC growth by down-regulation of HIF-1 alpha or. and beta-catenin via a PAK1-dependent pathway. (C) 2014 Elsevier B.V. All rights reserved.
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