Elevation of serum fortilin levels is specific for apoptosis and signifies cell death in vivo

Patuma Sinthujaroen, Nattaporn Wanachottrakul, Decha Pinkaew, John R. Petersen, Amornrat Phongdara, Melinda Sheffield-Moore, Kenichi Fujise

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background: Billions of cells undergo apoptosis each day in the average normal adult. The ability to readily assess the degree of apoptosis in human diseases is hampered by the lack of sensitive and specific serum biomarkers of apoptosis. Fortilin is a novel prosurvival molecule that protects cells against various noxious stimuli. While fortilin is secreted into the extracellular space under certain conditions, the relationship between the serum concentration of fortilin and the presence and extent of apoptosis in vivo remains unknown. Methods & results: Using a newly developed fortilin ELISA system, we show here that fortilin exists in the normal human and mouse circulation. We further demonstrate that fortilin serum levels are significantly elevated in patients with solid cancer, in response to anti-cancer chemo- or radiation therapy. The elevation of fortilin serum levels is more robust and sensitive than that of such previously-reported serum biomarkers of apoptosis as fragmented cytokeratin-18, cytochrome c, and nucleosomal DNA. In addition, targeted apoptotic liver damage induced by Jo2 anti-Fas (CD95) antibody consistently and significantly increased serum fortilin levels in C57BL/6J mice. Finally, when challenged by anti-human-Fas IgM antibody, Jurkat leukemic T cells apoptosed and released fortilin into the medium before plasma membrane integrity was compromised. Conclusions: Taken together, these data suggest that serum fortilin levels reflect the degree and extent of apoptosis occurring in vivo. General significance: Fortilin is a viable serum biomarker of in vivo apoptosis and can be utilized to noninvasively assess the status of in vivo apoptosis in humans.

Original languageEnglish (US)
Pages (from-to)103-111
Number of pages9
JournalBBA Clinical
Volume2
DOIs
StatePublished - Dec 1 2014

Fingerprint

Cell Death
Apoptosis
Serum
Biomarkers
Keratin-18
Antibodies
Extracellular Space
Cytochromes c
Inbred C57BL Mouse
Immunoglobulin M
Neoplasms
Radiotherapy
Enzyme-Linked Immunosorbent Assay
Cell Membrane
T-Lymphocytes
Liver
DNA

Keywords

  • Apoptosis
  • Biomarker
  • Fortilin
  • Programmed cell death

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Physiology (medical)
  • Molecular Medicine

Cite this

Elevation of serum fortilin levels is specific for apoptosis and signifies cell death in vivo. / Sinthujaroen, Patuma; Wanachottrakul, Nattaporn; Pinkaew, Decha; Petersen, John R.; Phongdara, Amornrat; Sheffield-Moore, Melinda; Fujise, Kenichi.

In: BBA Clinical, Vol. 2, 01.12.2014, p. 103-111.

Research output: Contribution to journalArticle

Sinthujaroen, P, Wanachottrakul, N, Pinkaew, D, Petersen, JR, Phongdara, A, Sheffield-Moore, M & Fujise, K 2014, 'Elevation of serum fortilin levels is specific for apoptosis and signifies cell death in vivo', BBA Clinical, vol. 2, pp. 103-111. https://doi.org/10.1016/j.bbacli.2014.10.002
Sinthujaroen P, Wanachottrakul N, Pinkaew D, Petersen JR, Phongdara A, Sheffield-Moore M et al. Elevation of serum fortilin levels is specific for apoptosis and signifies cell death in vivo. BBA Clinical. 2014 Dec 1;2:103-111. https://doi.org/10.1016/j.bbacli.2014.10.002
Sinthujaroen, Patuma ; Wanachottrakul, Nattaporn ; Pinkaew, Decha ; Petersen, John R. ; Phongdara, Amornrat ; Sheffield-Moore, Melinda ; Fujise, Kenichi. / Elevation of serum fortilin levels is specific for apoptosis and signifies cell death in vivo. In: BBA Clinical. 2014 ; Vol. 2. pp. 103-111.
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AU - Petersen, John R.

AU - Phongdara, Amornrat

AU - Sheffield-Moore, Melinda

AU - Fujise, Kenichi

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N2 - Background: Billions of cells undergo apoptosis each day in the average normal adult. The ability to readily assess the degree of apoptosis in human diseases is hampered by the lack of sensitive and specific serum biomarkers of apoptosis. Fortilin is a novel prosurvival molecule that protects cells against various noxious stimuli. While fortilin is secreted into the extracellular space under certain conditions, the relationship between the serum concentration of fortilin and the presence and extent of apoptosis in vivo remains unknown. Methods & results: Using a newly developed fortilin ELISA system, we show here that fortilin exists in the normal human and mouse circulation. We further demonstrate that fortilin serum levels are significantly elevated in patients with solid cancer, in response to anti-cancer chemo- or radiation therapy. The elevation of fortilin serum levels is more robust and sensitive than that of such previously-reported serum biomarkers of apoptosis as fragmented cytokeratin-18, cytochrome c, and nucleosomal DNA. In addition, targeted apoptotic liver damage induced by Jo2 anti-Fas (CD95) antibody consistently and significantly increased serum fortilin levels in C57BL/6J mice. Finally, when challenged by anti-human-Fas IgM antibody, Jurkat leukemic T cells apoptosed and released fortilin into the medium before plasma membrane integrity was compromised. Conclusions: Taken together, these data suggest that serum fortilin levels reflect the degree and extent of apoptosis occurring in vivo. General significance: Fortilin is a viable serum biomarker of in vivo apoptosis and can be utilized to noninvasively assess the status of in vivo apoptosis in humans.

AB - Background: Billions of cells undergo apoptosis each day in the average normal adult. The ability to readily assess the degree of apoptosis in human diseases is hampered by the lack of sensitive and specific serum biomarkers of apoptosis. Fortilin is a novel prosurvival molecule that protects cells against various noxious stimuli. While fortilin is secreted into the extracellular space under certain conditions, the relationship between the serum concentration of fortilin and the presence and extent of apoptosis in vivo remains unknown. Methods & results: Using a newly developed fortilin ELISA system, we show here that fortilin exists in the normal human and mouse circulation. We further demonstrate that fortilin serum levels are significantly elevated in patients with solid cancer, in response to anti-cancer chemo- or radiation therapy. The elevation of fortilin serum levels is more robust and sensitive than that of such previously-reported serum biomarkers of apoptosis as fragmented cytokeratin-18, cytochrome c, and nucleosomal DNA. In addition, targeted apoptotic liver damage induced by Jo2 anti-Fas (CD95) antibody consistently and significantly increased serum fortilin levels in C57BL/6J mice. Finally, when challenged by anti-human-Fas IgM antibody, Jurkat leukemic T cells apoptosed and released fortilin into the medium before plasma membrane integrity was compromised. Conclusions: Taken together, these data suggest that serum fortilin levels reflect the degree and extent of apoptosis occurring in vivo. General significance: Fortilin is a viable serum biomarker of in vivo apoptosis and can be utilized to noninvasively assess the status of in vivo apoptosis in humans.

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