Abstract 483: Docosahexaenoic acid inhibits heat shock protein 90 complex and client proteins by reducing intracellular ATP levels in breast and lung cancer
Authors: Mouradian Michael , Ma Irvin V. , Vicente Erika D. , Kikawa Keith D. , Chattin Amy M. , Pardini Ronald S. 
Published: May 2015

Abstract
A major contributor to carcinogenesis is the molecular chaperone heat shock protein 90 (Hsp90). Hsp90 regulates the proper folding and stabilization of several client proteins, including human epidermal growth factor receptor 2 (ErbB2) and hypoxia-inducible factor 1α (HIF-1α). ErbB2 is a member of the epidermal growth factor receptor (EGFR) family of receptor-proteins, and is a clinical target for the treatment of metastatic cancer, while HIF-1α is often stabilized and overexpressed in several cancers. The ability for Hsp90 to become a mature complex and to properly fold client proteins is dependent on adenosine triphosphate (ATP) binding with the co-chaperone, p23. Specific Hsp90 inhibitors, like geldanamycin, target the Hsp90 ATP-binding site to prevent formation of the mature complex. Although supplementation with docosahexaenoic acid (DHA; C22:6 n-3) has not been shown to specifically target the Hsp90 ATP-binding site, the current study demonstrates a similar effect by DHA causing a reduction in available intracellular ATP levels. DHA is the longest, most unsaturated omega-3 polyunsaturated fatty acid (PUFA) existing in biological membranes and has been shown to possess anti-cancer activity in several cancer models. Studies from our laboratory have shown that DHA enrichment can reduce cancer cell metabolism and intracellular ATP levels in both breast and lung cancer models. In this study, a novel mechanism for the ability of DHA to inhibit the Hsp90 chaperone complex is defined. In vitro analyses of BT-474 human breast ductal carcinoma, as well as the A549 human lung adenocarcinoma cell lines were used to determine the impact of DHA-induced decreases of intracellular ATP levels. We found that the reduction in ATP levels by DHA treatment resulted in significant decreases in the association of Hsp90 and p23 in both cell lines. The decreased association of the Hsp90-p23 complex led to decreased levels of ErbB2 and HIF-1α client proteins, suggesting that DHA can modify Hsp90 chaperone function and attenuate client protein levels. Additionally, similar results were found when employing 2-deoxyglucose (2-DG), a glycolytic inhibitor, which confirms that DHA and 2-DG can disrupt Hsp90 molecular chaperone function by decreasing cellular ATP levels. Consistent with these observations, when using a dose of DHA that did not significantly reduce intracellular ATP levels, no change in the Hsp90-p23 chaperone complex or protein levels of ErbB2 and HIF-1α were seen. These results demonstrate a potential use for dietary intervention to improve cancer therapy in tumors that overexpress Hsp90 client proteins.
Citation Format: Michael Mouradian, Irvin V. Ma, Erika D. Vicente, Keith D. Kikawa, Amy M. Chattin, Ronald S. Pardini. Docosahexaenoic acid inhibits heat shock protein 90 complex and client proteins by reducing intracellular ATP levels in breast and lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 483. doi:10.1158/1538-7445.AM2014-483