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Is There a Human Homologue to the Murine Proteolysis-Inducing Factor?

Authors' Affiliations: Departments of ¹ Oncology and ² Chemistry, University of Alberta, Edmonton, Alberta, Canada; ³ Tissue Injury and Repair Group, Clinical and Surgical Sciences (Surgery), University of Edinburgh, Edinburgh, United Kingdom; ⁴ Ciphergen Biosystems, Inc., Fremont, California; and ⁵ 2nd University Department of Cardiology, Atticon University Hospital, Athens, Greece

Requests for reprints: Vickie E. Baracos, Division of Palliative Care Medicine, Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, Canada T6G 1Z2. Phone: 1-780-432-8232; Fax: 1-780-432-8425; E-mail: vickieb{at}cancerboard.ab.ca.

Purpose: A tumor-derived proteolysis-inducing factor (PIF) is suggested to be a potent catabolic factor in skeletal muscle of mice and humans. We aimed to establish the clinical significance of PIF in cancer patients and to elucidate its structural features.

Experimental Design: PIF was detected in human urine using a monoclonal antibody (mAb) and related to clinical outcomes. PIF immunoaffinity-purified using the mAb was purified/separated using reverse-phase high-performance liquid chromatography and two-dimensional electrophoresis. Ten human cancer cell lines were tested for expression of mRNA encoding PIF core peptide.

Results: PIF immunoreactivity was present in 160 of 262 patients with advanced cancers of the lung, esophagus/stomach, and other organs. In a Kaplan-Meier survival analysis of 181 lung cancer patients, PIF was unrelated to survival; PIF status was also unrelated to skeletal muscle loss confirmed by computed tomography imaging. PIF was seen in 16 of 24 patients with chronic heart failure and thus is not exclusive to malignant disease. In-gel digestion and mass spectrometric analysis of immunoaffinity purified PIF from cancer patients consistently identified human albumin and immunoglobulins. We showed nonspecific binding of purified albumin and immunoglobulins to the anti-PIF mAb, which is thus not a useful tool for PIF detection or purification in humans. Finally, the human PIF core peptide was detected in human cancer cell lines using reverse transcription-PCR and nucleotide sequencing; however, none of the amplified products had a site for the glycosylation critical to the proteolysis-inducing activity of murine PIF.

Conclusions: A putative human homologue of murine PIF and its role in human cancer cachexia cannot be verified.

This article has been cited by other articles:

				M. J. Tisdale Re: Wieland BM, et al. Is There a Human Homologue to the Murine Proteolysis-Inducing Factor? Clin. Cancer Res., April 1, 2008; 14(7): 2245 - 2245. [Full Text] [PDF]

				V. E. Baracos Reply to Letter to the Editor: a Response to the Letter of M. Tisdale Clin. Cancer Res., April 1, 2008; 14(7): 2245 - 2245. [Full Text] [PDF]