Mitochondrial DNA mutation stimulates prostate cancer growth in bone stromal environment.
OBJECTIVE
Mitochondrial DNA (mtDNA) mutations, inherited and somatically acquired, are common in clinical prostate cancer. We have developed model systems designed to study specific mtDNA mutations in controlled experiments. Because prostate cancer frequently metastasizes to bone we tested the hypothesis that mtDNA mutations enhance prostate cancer growth and survival in the bone microenvironment.


METHODS
The pathogenic nucleotide position (np) 8993 mDNA mutation was introduced into PC3 prostate cancer cells by cybrid formation. Wild-type and mutant cybrids were grown as nude mouse subcutaneous xenografts with or without bone stromal cell co-inoculation. Cybrids were also grown in the intratibial space. Tumor growth was assayed by direct tumor measurement and luciferase chemiluminescence. Gene expression was assayed using cDNA microarrays confirmed by real time PCR, western blot analysis and immunohistochemistry.


RESULTS
Cybrids with the 8,993 mtDNA mutation grew faster than wild-type cybrids. Further growth acceleration was demonstrated in the bone microenvironment. A 37 gene molecular signature characterized the growth advantage conferred by the mtDNA mutation and bone microenvironment. Two genes of known importance in clinical prostate cancer, FGF1 and FAK, were found to be substantially upregulated only when both mtDNA mutation and bone stromal cell were present.


CONCLUSIONS
The ATP6 np 8,993 mtDNA mutation confers a growth advantage to human prostate cancer that is most fully manifest in the bone microenvironment. The identification of specific molecular alterations associated with mtDNA mutation and growth in bone may allow new understanding of prostate cancer bone metastasis.
Arnold
Rebecca S
RS
Department of Urology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Sun
Carrie Q
CQ
Richards
Jendai C
JC
Grigoriev
Galina
G
Coleman
Ilsa M
IM
Nelson
Peter S
PS
Hsieh
Chia-Ling
CL
Lee
Jae K
JK
Xu
Zhiheng
Z
Rogatko
Andre
A
Osunkoya
Adeboye O
AO
Zayzafoon
Majd
M
Chung
Leland
L
Petros
John A
JA
D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics* / Q000556:secondary*; D001842:Bone and Bones / Q000473:pathology; D002455:Cell Division; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D004272:DNA, Mitochondrial / Q000235:genetics*; D004195:Disease Models, Animal; D016220:Fibroblast Growth Factor 1 / Q000235:genetics / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D017154:Stromal Cells / Q000473:pathology; D014183:Transplantation, Heterologous
D004272:DNA, Mitochondrial; D016220:Fibroblast Growth Factor 1; D051416:Focal Adhesion Protein-Tyrosine Kinases