Abstract 998: Oncogenic potential of mitochondria regulate the cellular tumor characteristics

Abstract

Abstract Mitochondrial-nucleus cross-talks and mitochondrial retrograde regulation of nuclear genes can play significant role in cellular properties. Several studies reported that somatic mitochondrial DNA alterations are often detected in cancer cells. Most of such alterations are polymorphisms without functional significance. Here we use a transmitochondrial cybrid (cybrids) approach to understand the significance of mitochondrial property in regulating the oncogenic properties of a cell irrespective of its mutational and nuclear status. Cybrid models in two differently defined nuclear backgrounds were studied. In the first model, mitochondria depleted rho zero (≥0) from an aggressive osteosarcoma cell lines 143B TK− was used as a common nuclear background. 143B β0 cells were fused with mitochondria from non-cancerous breast epithelial cell line MCF10A, low metastatic breast cancer cell line MDA-MB-468 and highly metastatic 143B TK− cell lines. In the second model, we used the common nuclear background of A1N4, a non-tumorigenic immortalized breast epithelial cell. A1N4 β0 cells were fused with MCF-10A and metastatic breast cancer cells MDA-MB-231. Studies in parental mitochondrial donor cells suggested that cancer cell lines have reduced ATP synthesis, oxygen consumption and respiratory chain activities compared to non-cancerous cells. Interestingly, in spite of the common nuclear backgrounds, cybrids also showed properties similar to their parental cells under both cancerous and non-cancerous nuclear backgrounds. Functional studies in cybrids under non-cancerous nuclear background observed that fusion with cancerous mitochondria resulted in loss of growth contact inhibition, induction of colony formation potential in soft agar and increased survival potential under serum starvation. Similarly, functional studies in cybrids with cancerous nuclear background suggested that non-cancerous mitochondria could reverse different oncogenic characteristics of cancer cell including cell proliferation, viability under hypoxic condition, anti-apoptotic properties, resistance to anti-cancer drug, invasion, colony formation in soft agar, and in vivo tumor growth in nude mice. Microarray analysis of cybrids under cancerous nuclear background suggested that several oncogenic pathways are inhibited due to non-cancerous mitochondria. Interestingly, under non-cancerous nuclear background, induction of important oncogenes was observed in cybrids containing cancerous mitochondria. These results suggest that mitochondrial-nuclear cross talk have significant contribution to cancer cell properties. Also it highlights mitochondria as a promising target in cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 998. doi:1538-7445.AM2012-998