title: Crosstalk from non-cancerous mitochondria can inhibit tumor properties of metastatic cells by suppressing oncogenic pathways.
abstract: Mitochondrial-nucleus cross talks and mitochondrial retrograde regulation can play a significant role in cellular properties. Transmitochondrial cybrid systems (cybrids) are an excellent tool to study specific effects of altered mitochondria under a defined nuclear background. The majority of the studies using the cybrid model focused on the significance of specific mitochondrial DNA variations in mitochondrial function or tumor properties. However, most of these variants are benign polymorphisms without known functional significance. From an objective of rectifying mitochondrial defects in cancer cells and to establish mitochondria as a potential anticancer drug target, understanding the role of functional mitochondria in reversing oncogenic properties under a cancer nuclear background is very important. Here we analyzed the potential reversal of oncogenic properties of a highly metastatic cell line with the introduction of non-cancerous mitochondria. Cybrids were established by fusing the mitochondria DNA depleted 143B TK- ρ0 cells from an aggressive osteosarcoma cell line with mitochondria from benign breast epithelial cell line MCF10A, moderately metastatic breast cancer cell line MDA-MB-468 and 143B cells. In spite of the uniform cancerous nuclear background, as observed with the mitochondria donor cells, cybrids with benign mitochondria showed high mitochondrial functional properties including increased ATP synthesis, oxygen consumption and respiratory chain activities compared to cybrids with cancerous mitochondria. Interestingly, benign mitochondria could reverse different oncogenic characteristics of 143B TK(-) cell including cell proliferation, viability under hypoxic condition, anti-apoptotic properties, resistance to anti-cancer drug, invasion, and colony formation in soft agar, and in vivo tumor growth in nude mice. Microarray analysis suggested that several oncogenic pathways observed in cybrids with cancer mitochondria are inhibited in cybrids with non-cancerous mitochondria. These results suggest the critical oncogenic regulation by mitochondrial-nuclear cross talk and highlights rectifying mitochondrial functional properties as a promising target in cancer therapy.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. kaippare@bcm.edu
authors.forename: Benny Abraham
authors.initials: BA
authors.lastname: Kaipparettu
authors.forename: Yewei
authors.initials: Y
authors.lastname: Ma
authors.forename: Jun Hyoung
authors.initials: JH
authors.lastname: Park
authors.forename: Tin-Lap
authors.initials: TL
authors.lastname: Lee
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Patricia
authors.initials: P
authors.lastname: Yotnda
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.forename: Wai-Yee
authors.initials: WY
authors.lastname: Chan
authors.forename: Lee-Jun C
authors.initials: LJ
authors.lastname: Wong
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015687:Cell Hypoxia; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D064593:Heterografts; D006801:Humans; D006822:Hybrid Cells / Q000187:drug effects / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics
chemical_list: D000903:Antibiotics, Antineoplastic; D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D000255:Adenosine Triphosphate