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

Abstract

BackgroundBillions 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 & resultsUsing 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.ConclusionsTaken together, these data suggest that serum fortilin levels reflect the degree and extent of apoptosis occurring in vivo.General significanceFortilin is a viable serum biomarker of in vivo apoptosis and can be utilized to noninvasively assess the status of in vivo apoptosis in humans.

The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation

“…Another, more recent paper studied serum TCTP (fortilin) levels in mice and humans using a newly developed ELISA. The authors found that TCTP/ fortilin levels are significantly elevated in sera from patients with solid cancers, in response to chemo-or radiation therapy, and concluded that TCTP is suitable as a biomarker for apoptosis in vivo (Sinthujaroen et al 2014). …”

Fortilin: A Potential Target for the Prevention and Treatment of Human Diseases

“…Cancer cells undergo apoptosis at a higher rate than do normal cells and massively apoptose in response to radiation therapy and chemotherapy. Serum biomarkers of apoptosis could allow clinicians to screen patients for certain cancers and to monitor the response of patients with cancer to anti-cancer chemo- or radiation therapy [4]. …”

“…To test whether fortilin TCTP exists in the circulating blood, we devised a fortilin TCTP enzyme-linked immunosorbent assay (ELISA) assay system and found that fortilin TCTP circulates in the blood of both mice and humans at the concentration of 47.10 ±11.66 ng/mL and 75.57±45.79 ng/mL, respectively [4]. Fortilin TCTP , an intracellular anti-apoptotic molecule, is also released into the extracellular space via secretory exosomes [3].…”

“…Fortilin—also known as translationally controlled tumor protein (TCTP), histamine-releasing factor (HRF), and tumor protein translationally controlled 1 (TPT1)—is a 172-amino-acid multifunctional protein that exists in the cytosol [1], nucleus [1], mitochondria [2], extracellular space [3], and circulating blood [4]. Dimethyl sulfoxide (DMSO) causes mouse erythroleukemia (MEL) cells to halt the translation of several mRNAs as the cells undergo erythroid differentiation.…”

“…Herein we use the term fortilin TCTP . Fortilin comes from the Latin fortis (strong and robust) and is appropriate for the anti-apoptotic/pro-survival [1, 2, 4, 12–28], pro-growth/proliferative [29–39], calcium (Ca 2+ ) scavenging [17, 40, 41], and anti-pathogen activities [42–54] reported for the molecule.…”