Mitochondria are emerging as important players in the transformation process of cells, maintaining the biosynthetic and energetic capacities of cancer cells and serving as one of the primary sites of apoptosis and autophagy regulation. Although several avenues for cancer therapy have focused on mitochondria in recent years, progress in developing mitochondria-targeting anticancer drugs has nonetheless been slow. We have recently identified a key protein network that controls iron and reactive oxygen species (ROS) homeostasis in cancer cells and is required for tumor survival and proliferation in human epithelial breast cancer cells. Members of this network include novel proteins such as NAF-1 and mNT, as well as Bcl-2, and different tumor suppressor and tumor-associated proteins. Interestingly, several different members of the caged Garcinia xanthone cluvenone family of anticancer drugs, shown in clinical trials to be effective in breast cancer therapy, bind to and disrupt the function of different members of the protein network we identified (e.g., alter the stability of Fe-S clusters of NAF-1 and mNT). Because mitochondrial iron overload has been associated with different epithelial cancers including human breast cancer, and because proteins belonging to the network we identified accumulate to very high levels in these cancer cells, we hypothesize that targeting different members of the protein network that controls iron and ROS homeostasis in cells will prevent cancer cell proliferation and tumor growth, directly causing mitochondrial dysfunction and bypassing cancer cell resistance to apoptosis activation. In support of our hypothesis we have recently demonstrated that shRNA suppression of mNT or NAF-1 caused mitochondrial iron and ROS overload and suppressed cell proliferation of two different human breast cancer cell lines (MCF7 and MDA-231), as well as the growth of tumors in mice.
Our research goals include the following: a) The development of a novel anticancer treatment strategy that specifically targets iron and ROS homeostasis in cancer cells and bypasses cancer cell resistance to apoptosis and authophagy; b) The identification of new anticancer drug targets in the form of novel iron- and/or ROS-regulatory networks involved in cancer establishment and proliferation; c) The establishment of a new platform for the delivery of shRNA and/or different anticancer drugs to cells using nanoparticles. Our research is anticipated to identify key targets and pathways that will allow the development of therapeutic agents for the treatment of human epithelial breast cancer, including refractory breast cancer.
Bai F, Morcos F, Sohn YS, Darash-Yahana M, Rezende CO, Lipper CH, Paddock ML, Song L, Luo Y, Holt SH, Tamir S, Theodorakis EA, Jennings PA, Onuchic JN, Mittler R, Nechushtai R. The Fe-S cluster-containing NEET proteins mitoNEET and NAF-1 as chemotherapeutic targets in breast cancer. Proc Natl Acad Sci U S A. 2015 Mar 24;112(12):3698-703. doi: 10.1073/pnas.1502960112.
Tamir S, Paddock ML, Darash-Yahana-Baram M, Holt SH, Sohn YS, Agranat L, Michaeli D, Stofleth JT, Lipper CH, Morcos F, Cabantchik IZ, Onuchic JN, Jennings PA, Mittler R, Nechushtai R. Structure-function analysis of NEET proteins uncovers their role as key regulators of iron and ROS homeostasis in health and disease. Biochim Biophys Acta. 2015 Jun;1853(6):1294-315. doi: 10.1016/j.bbamcr.2014.10.014.
Tamir S, Eisenberg-Domovich Y, Conlan AR, Stofleth JT, Lipper CH, Paddock ML, Mittler R, Jennings PA, Livnah O, Nechushtai R. A point mutation in the [2Fe-2S] cluster binding region of the NAF-1 protein (H114C) dramatically hinders the cluster donor properties. Acta Crystallogr D Biol Crystallogr. 2014 Jun;70(Pt 6):1572-8. doi: 10.1107/S1399004714005458.
Tamir S, Zuris JA, Agranat L, Lipper CH, Conlan AR, Michaeli D, Harir Y, Paddock ML, Mittler R, Cabantchik ZI, Jennings PA, Nechushtai R. Nutrient-deprivation autophagy factor-1 (NAF-1): biochemical properties of a novel cellular target for anti-diabetic drugs. PLoS One. 2013 May 22;8(5):e61202. doi: 10.1371/journal.pone.0061202.
Nechushtai R, Conlan AR, Harir Y, Song L, Yogev O, Eisenberg-Domovich Y, Livnah O, Michaeli D, Rosen R, Ma V, Luo Y, Zuris JA, Paddock ML, Cabantchik ZI, Jennings PA, Mittler R. Characterization of Arabidopsis NEET reveals an ancient role for NEET proteins in iron metabolism. Plant Cell. 2012 May;24(5):2139-54. doi: 10.1105/tpc.112.097634.
Zuris JA, Harir Y, Conlan AR, Shvartsman M, Michaeli D, Tamir S, Paddock ML, Onuchic JN, Mittler R, Cabantchik ZI, Jennings PA, Nechushtai R. Facile transfer of [2Fe-2S] clusters from the diabetes drug target mitoNEET to an apo-acceptor protein. Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13047-52. doi: 10.1073/pnas.1109986108.