Proteolysis-inducing factor is expressed in tumours of patients with gastrointestinal cancers and correlates with weight loss

Cabal-Manzano, Rafael; Bhargava, Pankaj; Torres-Duarte, A.; Marshall, John L.; Wainer, Irving W.

doi:10.1054/bjoc.2001.1830

Cited by 79 publications

(64 citation statements)

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“…Muscle protein degradation in cancer cachexia appears to be associated with a sulphated glycoprotein of Mr 24 000 secreted by cachexia-inducing murine and human tumours (Todorov et al, 1996a;Cabal-Manzano et al, 2001). This substance is capable of inducing muscle protein breakdown directly, both in vitro and in vivo , and has been named proteolysis-inducing factor (PIF).…”

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confidence: 99%

Increased expression of the ubiquitin – proteasome pathway in murine myotubes by proteolysis-inducing factor (PIF) is associated with activation of the transcription factor NF-κB

2003

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Proteolysis-inducing factor (PIF), isolated from a cachexia-inducing murine tumour, has been shown to stimulate protein breakdown in C 2 C 12 myotubes. The effect was attenuated by the specific proteasome inhibitor lactacystin and there was an elevation of proteasome 'chymotrypsin-like' enzyme activity and expression of 20S proteasome a-subunits at concentrations of PIF between 2 and 16 nM. Higher concentrations of PIF had no effect. The action of PIF was attenuated by eicosapentaenoic acid (EPA) (50 mM). At a concentration of 4 nM, PIF induced a transient decrease in IkBa levels after 30 min incubation, while no effect was seen at 20 nM PIF. The level of IkBa, an NF-kB inhibitory protein, returned to normal after 60 min. Depletion of IkBa from the cytosol was not seen in myotubes pretreated with EPA, suggesting that the NF-kB/IkB complex was stabilised. At concentrations between 2 and 8 nM, PIF stimulated an increased nuclear migration of NF-kB, which was not seen in myotubes pretreated with EPA. The PIF-induced increase in chymotrypsin-like enzyme activity was also attenuated by the NF-kB inhibitor peptide SN50, suggesting that NF-kB may be involved in the PIF-induced increase in proteasome expression. The results further suggest that EPA may attenuate protein degradation induced by PIF, at least partly, by preventing NF-kB accumulation in the nucleus.

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confidence: 99%

Increased expression of the ubiquitin – proteasome pathway in murine myotubes by proteolysis-inducing factor (PIF) is associated with activation of the transcription factor NF-κB

2003

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Section: Proteolysis-inducing Factormentioning

confidence: 93%

“…Moreover, this compound was detected in the urine of 80% of pancreatic cancer patients with signiicantly higher total weight loss and rate of weight loss than those whose urine did not contain PIF [74]. Immunochemistry analysis also revealed the presence of PIF in the cytoplasm of GI tumors such as pancreatic adenocarcinoma [75].PIF has been found to induce cachectic symptoms when injected intravenously in normal mice; body composition analysis revealed that PIF extracted from the urine of cachectic cancer patients induced reductions in lean body mass without reduction in food and water intake in murine models [76]. This decrease in muscle mass involved two components: an increase in protein degradation by 50% and a reduction in protein synthesis by 50% observed in gastrocnemius muscle [77].…”

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confidence: 94%

Pancreatic Cancer Cachexia: Current Concepts and Clinical Management

Guan¹,

Shinde²,

Hendifar³

2017

Frailty and Sarcopenia - Onset, Development and Clinical Challenges

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There has been great progress over the last decade in understanding the pathophysiology of cachexia associated with pancreatic cancer. However, there is a large need to ind better therapeutic options to successfully manage this complex and challenging condition. Patients with pancreatic cancer have some of the highest prevalence and often the most severe degrees of cachexia, which is described as a multifactorial metabolic syndrome that is associated with unintended weight loss of adipose tissue and skeletal muscle in the seting of anorexia. This chapter will review the current concepts surrounding pancreatic cancer cachexia, its clinical diagnosis, pathophysiology, and its known and proposed therapeutics. A multimodal approach utilizing nutritional support and pharmaceutical therapies is proposed to lead to the most successful management of pancreatic cancer cachexia.Keywords: pancreatic cancer, cachexia, anorexia, metabolic syndrome, catabolism IntroductionIn western countries, pancreatic cancer represents the fourth leading cause of cancer-related death [1]. Among the many complications associated with this disease, cachexia marked by progressive weight loss represents one of the most distressing features related to pancreatic cancer. Cachexia is a multidimensional wasting syndrome that is characterized by unintended loss of both adipose tissue and lean body mass (LBM) that cannot be fully reversed through conventional nutritional support. It is a complex metabolic disorder frequently described in pancreatic cancer and represents a signiicant physical and psychological burden in approximately 80% of pancreatic cancer patients during the disease progression [2]. The complications © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. associated with cachexia, which include immobility, impaired immunity, and severe respiratory muscle impairment leading to cardiopulmonary failure, result in death in up to one-third of pancreatic cancer patients [3]. Cachectic patients are observed to have lower physical function, decreased tolerance to chemotherapy and radiation treatment, and generally worse prognosis than those with stable weight. Poorer outcomes after pancreaticoduodenectomy have also been observed in patients with preoperative signs of cachexia [4].While research over the past decade has provided new insights regarding the pathogenesis of pancreatic cancer cachexia, the mechanistic pathology of this condition is still not entirely understood. In this chapter, we will provide a review of the current concepts, potential therapeutic targets, and management of this signiicant clinical condition. Classiication and progression of cancer cachexiaCachexia has been established to be a common adverse efect of cancer. An international consensus in 2011 deined cachexia as a ...

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“…Instead, a tumor product, proteolysis-inducing factor (PIF), appears to be responsible for the loss of muscle mass (6), also through induction of key regulatory elements for proteasome proteolysis (7). PIF expression has been found in carcinomas of the prostate (8), colon, lung, esophagus, liver, and pancreas when weight loss is apparent (9) but not in normal prostate tissue or stromal cells. It previously has been shown that the action of PIF is attenuated by the polyunsaturated fatty acid eicosapentaenoic acid (EPA; ref.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of the Attenuation of Proteolysis-Inducing Factor Stimulated Protein Degradation in Muscle by β-Hydroxy-β-Methylbutyrate

2004

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The leucine metabolite ␤-hydroxy-␤-methylbutyrate (HMB) prevents muscle protein degradation in cancer-induced weight loss through attenuation of the ubiquitin-proteasome proteolytic pathway. To investigate the mechanism of this effect, the action of HMB on protein breakdown and intracellular signaling leading to increased proteasome expression by the tumor factor proteolysis-inducing factor (PIF) has been studied in vitro using murine myotubes as a surrogate model of skeletal muscle. A comparison has been made of the effects of HMB and those of eicosapentaenoic acid (EPA), a known inhibitor of PIF signaling. At a concentration of 50 mol/L, EPA and HMB completely attenuated PIF-induced protein degradation and induction of the ubiquitin-proteasome proteolytic pathway, as determined by the "chymotrypsin-like" enzyme activity, as well as protein expression of 20S proteasome ␣-and ␤-subunits and subunit p42 of the 19S regulator. The primary event in PIF-induced protein degradation is thought to be release of arachidonic acid from membrane phospholipids, and this process was attenuated by EPA, but not HMB, suggesting that HMB might act at another step in the PIF signaling pathway. EPA and HMB at a concentration of 50 mol/L attenuated PIF-induced activation of protein kinase C and the subsequent degradation of inhibitor B␣ and nuclear accumulation of nuclear factor B. EPA and HMB also attenuated phosphorylation of p42/44 mitogen-activated protein kinase by PIF, thought to be important in PIF-induced proteasome expression. These results suggest that HMB attenuates PIF-induced activation and increased gene expression of the ubiquitin-proteasome proteolytic pathway, reducing protein degradation.

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Proteolysis-inducing factor is expressed in tumours of patients with gastrointestinal cancers and correlates with weight loss

Cited by 79 publications

References 6 publications

Increased expression of the ubiquitin – proteasome pathway in murine myotubes by proteolysis-inducing factor (PIF) is associated with activation of the transcription factor NF-κB

Increased expression of the ubiquitin – proteasome pathway in murine myotubes by proteolysis-inducing factor (PIF) is associated with activation of the transcription factor NF-κB

Pancreatic Cancer Cachexia: Current Concepts and Clinical Management

Mechanism of the Attenuation of Proteolysis-Inducing Factor Stimulated Protein Degradation in Muscle by β-Hydroxy-β-Methylbutyrate

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