TIP-1 translocation onto the cell plasma membrane is a molecular biomarker of tumor response to ionizing radiation.
BACKGROUND
Tumor response to treatment has been generally assessed with anatomic and functional imaging. Recent development of in vivo molecular and cellular imaging showed promise in time-efficient assessment of the therapeutic efficacy of a prescribed regimen. Currently, the in vivo molecular imaging is limited with shortage of biomarkers and probes with sound biological relevance. We have previously shown in tumor-bearing mice that a hexapeptide (HVGGSSV) demonstrated potentials as a molecular imaging probe to distinguish the tumors responding to ionizing radiation (IR) and/or tyrosine kinase inhibitor treatment from those of non-responding tumors.


RESULTS
In this study we have studied biological basis of the HVGGSSV peptide binding within the irradiated tumors by use of tumor-bearing mice and cultured cancer cells. The results indicated that Tax interacting protein 1 (TIP-1, also known as Tax1BP3) is a molecular target that enables the selective binding of the HVGGSSV peptide within irradiated xenograft tumors. Optical imaging and immunohistochemical staining indicated that a TIP-1 specific antibody demonstrated similar biodistribution as the peptide in tumor-bearing mice. The TIP-1 antibody blocked the peptide from binding within irradiated tumors. Studies on both of human and mouse lung cancer cells showed that the intracellular TIP-1 relocated to the plasma membrane surface within the first few hours after exposure to IR and before the onset of treatment associated apoptosis and cell death. TIP-1 relocation onto the cell surface is associated with the reduced proliferation and the enhanced susceptibility to the subsequent IR treatment.


CONCLUSIONS
This study by use of tumor-bearing mice and cultured cancer cells suggested that imaging of the radiation-inducible TIP-1 translocation onto the cancer cell surface may predict the tumor responsiveness to radiation in a time-efficient manner and thus tailor radiotherapy of cancer.
Wang
Hailun
H
Department of Radiation Oncology, School of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America.
Yan
Heping
H
Fu
Allie
A
Han
Miaojun
M
Hallahan
Dennis
D
Han
Zhaozhong
Z
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000276:immunology; D000918:Antibody Specificity; D001667:Binding, Competitive; D015415:Biomarkers / Q000737:chemistry / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism* / Q000528:radiation effects*; D049109:Cell Proliferation / Q000528:radiation effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism / Q000528:radiation effects; D008780:Methyltransferases; D051379:Mice; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy*; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D054731:PDZ Domains; D021381:Protein Transport / Q000528:radiation effects
D000906:Antibodies; D015415:Biomarkers; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009842:Oligopeptides; C421249:TAX1BP3 protein, human; D008780:Methyltransferases; C503312:tension-induced inhibited protein, mouse