Cytotoxic stress induces transfer of mitochondria-associated human endogenous retroviral RNA and proteins between cancer cells

Abstract

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.

Expressional activation and functional roles of human endogenous retroviruses in cancers

“…Mitochondrial transfer from donor cells to cells of injured tissues is a promising cell‐based therapy that effectively brings about the recovery of tissue bioenergetics. Syncytin‐1/syncytin‐2 also function to mediate the cell‐to‐cell transfer of mitochondria, and this could be blocked by anti‐syncytin‐1 and anti‐syncytin‐2 antibodies …”

“…Syncytin-1/ syncytin-2 also function to mediate the cell-to-cell transfer of mitochondria, and this could be blocked by anti-syncytin-1 and antisyncytin-2 antibodies. 121 Huang et al demonstrated that Env proteins encoded by HERV-K could mediated intercellular fusion of melanoma cells, 122…”

Intercellular mitochondria trafficking highlighting the dual role of mesenchymal stem cells as both sensors and rescuers of tissue injury

“…They observed that, by simple co-incubation, chloramphenicol-(CAP s ) and efrapeptin-(EF s ) sensitive mammalian cells were able to incorporate mitochondria, purified beforehand from CAP r and EF r resistant cells [97]. Ever since, many cells have been reported to undergo mitochondrial transformation [55,[98][99][100][101][102]. This process is believed to occur via macropinocytosis.…”

Integral regulation of CHI3L1 gene and ERVW-1 locus expression by heparin in the gioblastoma cell lines U-87 MG and U-251 MG

“…Серед факторів, які зумовлюють таку регуляцію, можуть бути малі інтерферуючі РНК і альтернативний сплайсинг, який спричиняє продукцію ізоформи протеїну, що не впізнається комерційними антитілами. Синцитин-1 був виявлений для клітин U87 Dнaz-Carballo D. та співавторами [13], проте його продукція у ракових клітинах може бути причиною дезрегуляції на рівні транскрипції у результаті активації вутрішнього промотора. Таким чином, для вивчення регуляції експресії цих генів на рівні РНК і виявлення альтернативних ізоформ транскриптів цих генів ми обрали стратегію аналізу за допомогою праймерів до різних ділянок генів.…”