Growth inhibition of colon cancer cells by polyisoprenylated benzophenones is associated with induction of the endoplasmic reticulum response
Article first published online: 9 MAY 2008
Copyright © 2008 Wiley-Liss, Inc.
International Journal of Cancer
Volume 123, Issue 3, pages 687–694, 1 August 2008
How to Cite
Protiva, P., Hopkins, M. E., Baggett, S., Yang, H., Lipkin, M., Holt, P. R., Kennelly, E. J. and Bernard, W. I. (2008), Growth inhibition of colon cancer cells by polyisoprenylated benzophenones is associated with induction of the endoplasmic reticulum response. Int. J. Cancer, 123: 687–694. doi: 10.1002/ijc.23515
- Issue published online: 28 MAY 2008
- Article first published online: 9 MAY 2008
- Manuscript Accepted: 18 JAN 2008
- Manuscript Received: 9 JUL 2007
- NCI. Grant Number: CA-29502-24
- The Irwing Weinstein Foundation, Inc.
- New Investigator Award of the Clinical Nutrition Research Unit, NIH
- Garcinia xanthochymus;
- endoplasmic reticulum stress;
- unfolded protein;
- cell cycle arrest
Polyisoprenylated benzophenones derived from Garcinia xanthochymus have cytotoxic activity in vitro and antitumor activity in rodent models, but the mechanism is unknown. The purpose of our study was to examine in parallel molecular pathways that are targeted by 3 Garcinia-derived benzophenones-xanthochymol (X), guttiferone E (GE) and guttiferone H (GH), in 3 human colon cancer cell lines, HCT116, HT29 and SW480. The IC50 concentrations were determined and the cells were then treated with X, GE or GH at their respective IC50 or IC50x2 concentrations. Effects on the cell cycle, mitochondrial membrane potential and apoptosis were assessed by flow cytometry and caspase activation. Changes in gene expression were assessed with Illumina 24 K gene arrays. We found that X, GE and GH induced loss of mitochondrial membrane potential and G1 arrest at their IC50 concentrations and induced caspase activation at IC50 × 2 concentrations. An analysis of the changes in gene expression revealed that with all 3 compounds and all 3 cell lines there was a marked increase in expression of several genes, including XBP1, ATF4 and DDIT3/CHOP, which are components of the endoplasmic reticulum stress response. The DDIT4/REDD1 gene, an inhibitor of the mTOR survival pathway, was also up-regulated. Therefore, X, GE and GH appear to inhibit the growth of human colon cancer cells, at least in part, by activating the endoplasmic reticulum stress response and inhibiting the mTOR cell survival pathway. These combined effects may contribute to the anticancer activity of these novel compounds. © 2008 Wiley-Liss, Inc.