Cytotoxic stress induces transfer of mitochondria-associated human endogenous retroviral RNA and proteins between cancer cells
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David Díaz-Carballo1, Jacqueline Klein1, Ali H. Acikelli1, Camilla Wilk1, Sahitya Saka1, Holger Jastrow2, Gunther Wennemuth2, Phillip Dammann3, Urs Giger-Pabst4, Veria Khosrawipour4, Joachim Rassow5, Mikalai Nienen6 and Dirk Strumberg1
1Institute for Molecular Oncology and Experimental Therapeutics, Department of Hematology and Medical Oncology, Marienhospital Herne, Ruhr-University of Bochum, Bochum, Germany
2Institute of Anatomy and Experimental Morphology, University of Duisburg-Essen, Essen, Germany
3Central Animal Laboratory, University of Duisburg-Essen, Essen, Germany
4Department of Surgery, Marienhospital Herne, Ruhr-University of Bochum, Bochum, Germany
5Institute of Biochemistry and Pathobiochemistry, Department of Cellular Biochemistry, Ruhr-University of Bochum, Bochum, Germany
6Department of Nephrology, Marienhospital Herne, Ruhr-University of Bochum, Bochum, Germany
David Díaz-Carballo, email: [email protected]spital-herne.de
Keywords: human endogenous retroviruses (HERVs); mitochondria; intercellular mitochondrial transfer; syncytin-1/2 receptors
Received: October 27, 2016 Accepted: August 25, 2017 Published: October 07, 2017
About 8 % of the human genome consists of human endogenous retroviruses (HERVs), which are relicts of ancient exogenous retroviral infections incurred during evolution. Although the majority of HERVs have functional gene defects or epigenetic modifications, many of them are still able to produce retroviral proteins that have been proposed to be involved in cellular transformation and cancer development.
We found that, in chemo-resistant U87RETO glioblastoma cells, cytotoxic stress induced by etoposide promotes accumulation and large-scale fission of mitochondria, associated with the detection of HERV-WE1 (syncytin-1) and HERV-FRD1 (syncytin-2) in these organelles. In addition, mitochondrial preparations also contained the corresponding receptors, i.e. ASCT2 and MFSD2. We clearly demonstrated that mitochondria associated with HERV-proteins were shuttled between adjacent cancer cells not only via tunneling tubes, but also by direct cellular uptake across the cell membrane. Furthermore, anti-syncytin-1 and anti-syncytin-2 antibodies were able to specifically block this direct cellular uptake of mitochondria even more than antibodies targeting the cognate receptors.
Here, we suggest that the association of mitochondria with syncytin-1/syncytin-2 together with their respective receptors could represent a novel mechanism of cell-to-cell transfer. In chemotherapy-refractory cancer cells, this might open up attractive avenues to novel mitochondria-targeting therapies.
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