Mitochondrial DNA mutation stimulates prostate cancer growth in bone stromal environment

Rebecca S. Arnold, Carrie Q. Sun, Jendai C. Richards, Galina Grigoriev, Ilsa M. Coleman, Peter S. Nelson, Chia Ling Hsieh, Jae K. Lee, Zhiheng Xu, Andre Rogatko, Adeboye O. Osunkoya, Majd Zayzafoon, Leland Chung, John A. Petros

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

BACKGROUND AND OBJECTIVES. 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.

Original languageEnglish
Pages (from-to)1-11
Number of pages11
JournalProstate
Volume69
Issue number1
DOIs
Publication statusPublished - Jan 1 2009
Externally publishedYes

Fingerprint

Bone Development
Mitochondrial DNA
Prostatic Neoplasms
Mutation
Bone and Bones
Growth
Stromal Cells
Nucleotides
Luminescent Measurements
Fibroblast Growth Factor 1
Bone Neoplasms
Oligonucleotide Array Sequence Analysis
Luciferases
Heterografts
Nude Mice
Genes
Real-Time Polymerase Chain Reaction
Neoplasms
Western Blotting
Immunohistochemistry

Keywords

  • Cybrid
  • FAK
  • FGF1
  • Metastasis

ASJC Scopus subject areas

  • Urology
  • Oncology
  • Medicine(all)

Cite this

Arnold, R. S., Sun, C. Q., Richards, J. C., Grigoriev, G., Coleman, I. M., Nelson, P. S., ... Petros, J. A. (2009). Mitochondrial DNA mutation stimulates prostate cancer growth in bone stromal environment. Prostate, 69(1), 1-11. https://doi.org/10.1002/pros.20854

Mitochondrial DNA mutation stimulates prostate cancer growth in bone stromal environment. / Arnold, Rebecca S.; Sun, Carrie Q.; Richards, Jendai C.; Grigoriev, Galina; Coleman, Ilsa M.; Nelson, Peter S.; Hsieh, Chia Ling; Lee, Jae K.; Xu, Zhiheng; Rogatko, Andre; Osunkoya, Adeboye O.; Zayzafoon, Majd; Chung, Leland; Petros, John A.

In: Prostate, Vol. 69, No. 1, 01.01.2009, p. 1-11.

Research output: Contribution to journalArticle

Arnold, RS, Sun, CQ, Richards, JC, Grigoriev, G, Coleman, IM, Nelson, PS, Hsieh, CL, Lee, JK, Xu, Z, Rogatko, A, Osunkoya, AO, Zayzafoon, M, Chung, L & Petros, JA 2009, 'Mitochondrial DNA mutation stimulates prostate cancer growth in bone stromal environment', Prostate, vol. 69, no. 1, pp. 1-11. https://doi.org/10.1002/pros.20854
Arnold RS, Sun CQ, Richards JC, Grigoriev G, Coleman IM, Nelson PS et al. Mitochondrial DNA mutation stimulates prostate cancer growth in bone stromal environment. Prostate. 2009 Jan 1;69(1):1-11. https://doi.org/10.1002/pros.20854
Arnold, Rebecca S. ; Sun, Carrie Q. ; Richards, Jendai C. ; Grigoriev, Galina ; Coleman, Ilsa M. ; Nelson, Peter S. ; Hsieh, Chia Ling ; Lee, Jae K. ; Xu, Zhiheng ; Rogatko, Andre ; Osunkoya, Adeboye O. ; Zayzafoon, Majd ; Chung, Leland ; Petros, John A. / Mitochondrial DNA mutation stimulates prostate cancer growth in bone stromal environment. In: Prostate. 2009 ; Vol. 69, No. 1. pp. 1-11.
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AU - Nelson, Peter S.

AU - Hsieh, Chia Ling

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AU - Xu, Zhiheng

AU - Rogatko, Andre

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AB - BACKGROUND AND OBJECTIVES. 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.

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