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

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.

[1]  A. Vigano,et al.  Clinical survival predictors in patients with advanced cancer. , 2000, Archives of internal medicine.

[2]  H. Friess,et al.  The presence of the proteolysis-inducing factor in urine does not predict the malignancy of a pancreatic tumour , 2005, BMC gastroenterology.

[3]  Nikolaus Blin,et al.  Dermcidin: a novel human antibiotic peptide secreted by sweat glands , 2001, Nature Immunology.

[4]  C. Garbe,et al.  Specifically regulated genes in malignant melanoma tissues identified by subtractive hybridization , 2000, British Journal of Cancer.

[5]  R. Chlebowski,et al.  Gender influence on weight‐loss pattern and survival of nonsmall cell lung carcinoma patients , 1996, Cancer.

[6]  I. Wainer,et al.  Investigation of the potential of capillary electrophoresis with off-line matrix-assisted laser desorption/ionization time-of-flight mass spectrometry for clinical analysis: examination of a glycoprotein factor associated with cancer cachexia. , 1999, Analytical chemistry.

[7]  J. Jen,et al.  Characterization of a Human Homologue of Proteolysis-Inducing Factor and Its Role in Cancer Cachexia , 2004, Clinical Cancer Research.

[8]  M. Tisdale,et al.  Structural Analysis of a Tumor-produced Sulfated Glycoprotein Capable of Initiating Muscle Protein Degradation* , 1997, The Journal of Biological Chemistry.

[9]  T. J. Cunningham,et al.  Identification of the Human cDNA for New Survival/Evasion Peptide (DSEP): Studies in Vitro and in Vivo of Overexpression by Neural Cells , 2002, Experimental Neurology.

[10]  M. Tisdale,et al.  Induction of muscle protein degradation and weight loss by a tumor product. , 1996, Cancer research.

[11]  J. Marshall,et al.  Proteolysis-inducing factor is expressed in tumours of patients with gastrointestinal cancers and correlates with weight loss , 2001, British Journal of Cancer.

[12]  N. Foster,et al.  The proteolysis-inducing factor: in search of its clinical relevance in patients with metastatic gastric/esophageal cancer. , 2006, Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus.

[13]  K. Fearon,et al.  Characteristics of patients with pancreatic cancer expressing a novel cancer cachectic factor , 2000, The British journal of surgery.

[14]  Stanley Heshka,et al.  Total body skeletal muscle and adipose tissue volumes: estimation from a single abdominal cross-sectional image. , 2004, Journal of applied physiology.

[15]  D. He,et al.  [Establishment of bone metastasis model of prostate cancer in nude mice by intratibia injection of human prostate cancer cell line Du145]. , 2006, Zhonghua nan ke xue = National journal of andrology.

[16]  K. Fearon,et al.  Reply: Expression of the proteolysis-inducing factor core-peptide mRNA is upregulated in both tumour and adjacent normal tissue in gastrooesophageal malignancy , 2007, British Journal of Cancer.

[17]  S. Yokoyama,et al.  Characterization of the N-oligosaccharides attached to the atypical Asn-X-Cys sequence of recombinant human epidermal growth factor receptor. , 2000, Journal of biochemistry.

[18]  O. Jensen,et al.  Optimized preparation of urine samples for two-dimensional electrophoresis and initial application to patient samples. , 2002, Clinical biochemistry.

[19]  M. Tisdale,et al.  Induction of muscle protein degradation by a tumour factor. , 1997, British Journal of Cancer.

[20]  C. Begg,et al.  Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. , 1980, The American journal of medicine.

[21]  P. Levitt,et al.  Identification of a Survival-Promoting Peptide in Medium Conditioned by Oxidatively Stressed Cell Lines of Nervous System Origin , 1998, The Journal of Neuroscience.

[22]  U. K. Laemmli,et al.  Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4 , 1970, Nature.

[23]  K. Fearon,et al.  Characterization of a cancer cachectic factor , 1996, Nature.

[24]  A. Negassa,et al.  Prognostic importance of weight loss in chronic heart failure and the effect of treatment with angiotensin-converting-enzyme inhibitors: an observational study☆ , 2003 .

[25]  Yuqin Dai,et al.  Two-layer sample preparation: a method for MALDI-MS analysis of complex peptide and protein mixtures. , 1999, Analytical chemistry.

[26]  I. Waddell,et al.  Dermcidin expression in hepatic cells improves survival without N-glycosylation, but requires asparagine residues , 2006, British Journal of Cancer.

[27]  M. Tisdale,et al.  Mechanism of muscle protein degradation induced by a cancer cachectic factor. , 1998, British Journal of Cancer.

[28]  J. Ajani,et al.  Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. , 1998, The New England journal of medicine.

[29]  J. Marshall,et al.  The Relationship Between a Urinary Cachectic Factor and Weight Loss in Advanced Cancer Patients , 2004, Cancer investigation.

[30]  Joseph R. Bertino,et al.  Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. , 1980, The American journal of medicine.

[31]  Bodo E. Knudsen,et al.  Surface‐enhanced laser desorption/ionization‐time of flight‐mass spectrometry (SELDI‐TOF‐MS): A new proteomic urinary test for patients with urolithiasis , 2004, Journal of clinical laboratory analysis.

[32]  Shui-Tein Chen,et al.  Different techniques for urinary protein analysis of normal and lung cancer patients , 2005, Proteomics.

[33]  S B Heymsfield,et al.  Cadaver validation of skeletal muscle measurement by magnetic resonance imaging and computerized tomography. , 1998, Journal of applied physiology.

[34]  M. Tisdale,et al.  Role of a proteolysis-inducing factor (PIF) in cachexia induced by a human melanoma (G361) , 1999, British Journal of Cancer.

[35]  M. Tisdale,et al.  Effect of a cancer cachectic factor on protein synthesis/degradation in murine C2C12 myoblasts: modulation by eicosapentaenoic acid. , 1999, Cancer research.

[36]  R. Vessella,et al.  Expression of the human cachexia‐associated protein (HCAP) in prostate cancer and in a prostate cancer animal model of cachexia , 2003, International journal of cancer.

[37]  K. Fearon,et al.  Expression of the proteolysis-inducing factor core peptide mRNA is upregulated in both tumour and adjacent normal tissue in gastro-oesophageal malignancy , 2006, British Journal of Cancer.

[38]  M. Tisdale,et al.  Induction of cachexia in mice by a product isolated from the urine of cachectic cancer patients. , 1997, British Journal of Cancer.

[39]  M. Tisdale,et al.  NF-κB mediates proteolysis-inducing factor induced protein degradation and expression of the ubiquitin–proteasome system in skeletal muscle , 2005, British Journal of Cancer.