TY - JOUR
T1 - Elevation of serum fortilin levels is specific for apoptosis and signifies cell death in vivo
AU - Sinthujaroen, Patuma
AU - Wanachottrakul, Nattaporn
AU - Pinkaew, Decha
AU - Petersen, John R.
AU - Phongdara, Amornrat
AU - Sheffield-Moore, Melinda
AU - Fujise, Ken
N1 - Funding Information:
We thank Ms. Heather W. Foster for her editorial support in manuscript preparation, Dr. David Konkel for critically editing the manuscript and Ms. Glenda C. Brents for her help with the graphical abstract. This study was conducted with the support of the Institute for Translational Sciences at the University of Texas Medical Branch (supported in part by a Clinical and Translational Science Award ( UL1TR000071 ) from the National Center for Advancing Translational Sciences, National Institutes of Health) , a grant from the National Cancer Institute ( 5R01CA127971 , to M.S.M.), a grant from the National Heart Lung and Blood Institute ( R01HL117247 to K.F.), and a grant from the Thailand Research Fund through the Royal Golden Jubilee Ph.D. Graduate Program (Grant No. PHD/0041/2549 , to P.S.).
Publisher Copyright:
© 2014 The Authors.
PY - 2014/12/1
Y1 - 2014/12/1
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.
KW - Apoptosis
KW - Biomarker
KW - Fortilin
KW - Programmed cell death
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U2 - 10.1016/j.bbacli.2014.10.002
DO - 10.1016/j.bbacli.2014.10.002
M3 - Article
AN - SCOPUS:84913549383
SN - 2214-6474
VL - 2
SP - 103
EP - 111
JO - BBA Clinical
JF - BBA Clinical
ER -