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Re: Wieland BM, et al. Is There a Human Homologue to the Murine Proteolysis–Inducing Factor?

Nutritional Biomedicine, School of Life and Health Sciences, Aston University, Birmingham B4 7ET, United Kingdom

In Response: Wieland et al. (1) have examined the role of proteolysis-inducing factor (PIF) in human cancer cachexia by Western blotting of total urinary proteins using a monoclonal antibody, which is directed to the sulfated oligosaccharide chains (2). However, it is unlikely that they were measuring PIF, in view of the cross-reactivity of this antibody to immunoglobulin light chains. This is not surprising considering the low affinity of the antibody for PIF (Kaff 10⁸M^–1) and the limiting number of structural motifs on oligosaccharides, which in PIF bear some resemblance to chondroitin sulfate (2). Although the antibody is monoclonal, it was produced by fusion of splenocytes from mice bearing the MAC16 tumor without administration of antigen (3). Most recent studies have either confirmed that the band appearing at 24 kDa in the Western blots was PIF by using an antibody to the polypeptide core (4) or have fractionated the urine by capillary electrophoresis before mass spectrometry (5). These studies were not referenced in the above article, which is surprising because the results of the latter study showed the opposite result, which is cancer patients who were positive for PIF experienced weight loss, whereas PIF-negative patients gained weight (5). In addition to the lack of confirmation that the material being measured was PIF, there seems to be only one measurement of the PIF status of the patients. This is important because in the longitudinal studies (5), four repeated measures were made during a 2.5-year period, and there was a change in PIF status in 41% of the patients with 19% changing from negative to positive, 8% changing from positive to negative, and 14% varying during the course of the study. This change in PIF status could have happened in the above study. PIF concentrations in urine are very low (500 ng/L, representing 5 x 10^–4% of total cellular protein), and it is unlikely to be in the major bands as reported. However, other workers (6) have successfully purified PIF from human urine and have shown it to be identical to recombinant PIF.

The authors question whether glycosylated PIF could exist based on the lack of a conventional N- and O-glycosylation sequence in the PIF core peptide. However, fully glycosylated recombinant PIF has been reported (6), and glycosylated PIF has been detected in bone, liver, and lymph node metastases as well as urine of cachectic patients using an antibody to both the core peptide, and to the oligosaccharide chains (4).

References

1. Wieland BM, Stewart GD, Skipworth RJE, et al. Is there a human homologue to the murine proteolysis-inducing factor? Clin Cancer Res 2007;13:4984–92.[Abstract/Free Full Text]
2. Todorov PT, Deacon M, Tisdale MJ. Structural analysis of a tumor-produced sulfated glycoprotein capable of initiating muscle protein degradation. J Biol Chem 1997;272:12279–88.[Abstract/Free Full Text]
3. Todorov PT, McDevitt TM, Cariuk P, Coles B, Deacon M, Tisdale MJ. Induction of muscle protein degradation and weight loss by a tumor product. Cancer Res 1996;56:1256–61.[Abstract/Free Full Text]
4. Wang Z, Corey E, Hass GM, et al. Expression of the human cachexia-associated protein (HCAP) in prostate cancer and in a prostate cancer animal model of cachexia. Int J Cancer 2003;105:123–9.[CrossRef][Medline]
5. Williams ML, Torres-Duarte A, Brant LJ, Bhargava P, Marshall J, Wainer IW. The relationship between a urinary cachectic factor and weight loss in advanced cancer patients. Cancer Invest 2004;22:868–70.
6. Watchorn T, Waddell I, Ross JA. Proteolysis-inducing factor differentially influences transcriptional regulation in endothelian subtypes. Am J Physiol Endocrinol Metab 2002;282:E763–9.[Abstract/Free Full Text]

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