Search

The purpose of this study was to ascertain the mechanisms by which advanced prostate cancer cells resist bortezomib therapy. Several independent studies have shown that cells are protected from proteasome inhibition by increased autophagic activity. We investigated whether C/EBPβ, a transcription factor involved in the control of autophagic gene expression, regulates resistance to proteasome inhibition. In PC3 cells over-expressing C/EBPβ, turnover of autophagic substrates and expression of core autophagy genes were increased. Conversely, C/EBPβ knockdown suppressed autophagosome-lysosome fusion. We also found that C/EBPβ knockdown suppressed REDD1 expression to delay early autophagy, an effect rescued by exogenous REDD1. Cells with suppressed C/EBPβ levels showed delayed autophagy activation upon bortezomib treatment. Knockdown of C/EBPβ sensitized PC3 cells to bortezomib, and blockade of autophagy by chloroquine did not further increase cell death in cells expressing shRNA targeting C/EBPβ. Lastly, we observed a decreased growth of PC3 cells and xenografts with C/EBPβ knockdown and such xenografts were sensitized to bortezomib treatment. Our results demonstrate that C/EBPβ is a critical effector of autophagy via regulation of autolysosome formation and promotes resistance to proteasome inhibitor treatment by increasing autophagy., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Dietary unsaturated fatty acids have been implicated in breast cancer. Since mutations in BRCA1 gene are known to predispose to breast cancers, and BRCA1 gene is known to be regulated by estradiol, the effect of linoleic acid, an omega-6-polyunsaturated fatty acid, with and without estradiol was studied for the expression of BRCA1 gene, in MCF-7 cell line, which has only one wild type allele. MCF-7 cells exposed to either linoleic acid or estradiol showed relatively greater number of colonies on soft agar, extent of proliferation and BRCA1 mRNA expression compared with controls. However, cells treated with both linoleic acid and estradiol showed significantly higher number of colonies, proliferation index and appreciably decreased expression of BRCA1 mRNA compared with controls or cells treated with linoleic acid or estradiol alone. The synergistic effects of these two agents were abrogated when indomethacin, an inhibitor of prostaglandin pathway, was added to the culture. From these observations it appears that diet rich in omega-6-polyunsaturated fatty acid like linoleic acid and endogenous estrogen may modulate BRCA1 gene expression thereby promoting breast cancer.