Increased Muscle Proteasome Activity Correlates With Disease Severity in Gastric Cancer Patients

ObjectiveTo investigate the state of activation of the ATP-ubiquitin-dependent proteolytic system in the skeletal muscle of gastric cancer patients. Summary Background DataMuscle wasting in experimental cancer cachexia is frequently associated with hyperactivation of the ATP-dependent ubiquitin-proteasome proteolytic system. Increased muscle ubiquitin mRNA levels have been previously shown in gastric cancer patients, suggesting that this proteolytic system might be modulated also in human cancer. MethodsBiopsies of the rectus abdominis muscle were obtained intraoperatively from 23 gastric cancer patients and 14 subjects undergoing surgery for benign abdominal diseases, and muscle ubiquitin mRNA expression and proteasome proteolytic activities were assessed. ResultsMuscle ubiquitin mRNA was hyperexpressed in gastric cancer patients compared to controls. In parallel, three proteasome proteolytic activities (CTL, chymotrypsin-like; TL, trypsin-like; PGP, peptidyl-glutamyl-peptidase) significantly increased in gastric cancer patients with respect to controls. Advanced tumor stage, poor nutritional status, and age more than 50 years were associated with significantly higher CTL activity but had no influence on TL and PGP activity. ConclusionsThese results confirm the involvement of the ubiquitin-proteasome proteolytic system in the pathogenesis of muscle protein hypercatabolism in cancer cachexia. The observation that perturbations of this pathway in gastric cancer patients occur even before clinical evidence of body wasting supports the thinking that specific pharmacologic and metabolic approaches aimed at counteracting the upregulation of this pathway should be undertaken as early as cancer is diagnosed.

[1]  M. Tisdale,et al.  Downregulation of ubiquitin-dependent proteolysis by eicosapentaenoic acid in acute starvation. , 2001, Biochemical and biophysical research communications.

[2]  M. Tisdale,et al.  Activation of ATP-ubiquitin-dependent proteolysis in skeletal muscle in vivo and murine myoblasts in vitro by a proteolysis-inducing factor (PIF) , 2001, British Journal of Cancer.

[3]  R. Bellantone,et al.  Increased muscle ubiquitin mRNA levels in gastric cancer patients. , 2001, American journal of physiology. Regulatory, integrative and comparative physiology.

[4]  A. Goldberg,et al.  What do we really know about the ubiquitin-proteasome pathway in muscle atrophy? , 2001, Current opinion in clinical nutrition and metabolic care.

[5]  P. Costelli,et al.  Activation of Ca2+-dependent proteolysis in skeletal muscle and heart in cancer cachexia , 2001, British Journal of Cancer.

[6]  J. Fischer,et al.  Muscle Cachexia: Current Concepts of Intracellular Mechanisms and Molecular Regulation , 2001, Annals of surgery.

[7]  R. Bellantone,et al.  Serum tumour necrosis factor‐α levels in cancer patients are discontinuous and correlate with weight loss , 2000, European journal of clinical investigation.

[8]  P. Hasselgren,et al.  Burn injury upregulates the activity and gene expression of the 20 S proteasome in rat skeletal muscle , 2000 .

[9]  P. Costelli,et al.  Cancer cachexia: from experimental models to patient management. , 2000, Current opinion in clinical nutrition and metabolic care.

[10]  J. Fischer,et al.  The expression of genes in the ubiquitin-proteasome proteolytic pathway is increased in skeletal muscle from patients with cancer. , 1999, Surgery.

[11]  J. Fischer,et al.  Sepsis stimulates release of myofilaments in skeletal muscle by a calcium‐dependent mechanism , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[12]  J. Fischer,et al.  Activity and expression of the 20S proteasome are increased in skeletal muscle during sepsis. , 1999, American journal of physiology. Regulatory, integrative and comparative physiology.

[13]  E. Sausville,et al.  Proteasome inhibitors: a novel class of potent and effective antitumor agents. , 1999, Cancer research.

[14]  Keiji Tanaka,et al.  Manipulation of the ubiquitin-proteasome pathway in cachexia: pentoxifylline suppresses the activation of 20S and 26S proteasomes in muscles from tumor-bearing rats , 1999, Molecular Biology Reports.

[15]  F. López‐Soriano,et al.  Tumour growth and nitrogen metabolism in the host (Review). , 1999, International journal of oncology.

[16]  N. Agell,et al.  Different cytokines modulate ubiquitin gene expression in rat skeletal muscle. , 1998, Cancer letters.

[17]  J. Wang,et al.  Proteasome blockers inhibit protein breakdown in skeletal muscle after burn injury in rats. , 1998, Clinical science.

[18]  N. Agell,et al.  Ubiquitin and proteasome gene expression is increased in skeletal muscle of slim AIDS patients. , 1998, International journal of molecular medicine.

[19]  G. Cohen,et al.  Proteasome activities decrease during dexamethasone-induced apoptosis of thymocytes. , 1998, The Biochemical journal.

[20]  A. Goldberg,et al.  Inhibitors of the proteasome reduce the accelerated proteolysis in atrophying rat skeletal muscles. , 1997, The Journal of clinical investigation.

[21]  N. Agell,et al.  The ubiquitin system: A role in disease? , 1997, Medicinal research reviews.

[22]  T. Meyer,et al.  Sepsis is associated with increased mRNAs of the ubiquitin-proteasome proteolytic pathway in human skeletal muscle. , 1997, The Journal of clinical investigation.

[23]  L. Tessitore,et al.  Anti-TNF treatment reverts increased muscle ubiquitin gene expression in tumour-bearing rats. , 1996, Biochemical and biophysical research communications.

[24]  B. Beaufrère,et al.  Increased mRNA levels for components of the lysosomal, Ca2+-activated, and ATP-ubiquitin-dependent proteolytic pathways in skeletal muscle from head trauma patients. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[25]  W. Mitch,et al.  The acidosis of chronic renal failure activates muscle proteolysis in rats by augmenting transcription of genes encoding proteins of the ATP-dependent ubiquitin-proteasome pathway. , 1996, The Journal of clinical investigation.

[26]  L. Tessitore,et al.  Muscle protein waste in tumor-bearing rats is effectively antagonized by a beta 2-adrenergic agonist (clenbuterol). Role of the ATP-ubiquitin-dependent proteolytic pathway. , 1995, The Journal of clinical investigation.

[27]  A. Goldberg,et al.  Activation of the ATP-ubiquitin-proteasome pathway in skeletal muscle of cachectic rats bearing a hepatoma. , 1995, The American journal of physiology.

[28]  N. Agell,et al.  Muscle wasting associated with cancer cachexia is linked to an important activation of the atp‐dependent ubiquitin‐mediated proteolysis , 1995, International journal of cancer.

[29]  J. Estrela,et al.  Increased ATP-ubiquitin-dependent proteolysis in skeletal muscles of tumor-bearing rats. , 1994, Cancer research.

[30]  N. Agell,et al.  Ubiquitin gene expression is increased in skeletal muscle of tumour‐bearing rats , 1994, FEBS letters.

[31]  L. Tessitore,et al.  Tumor necrosis factor-alpha mediates changes in tissue protein turnover in a rat cancer cachexia model. , 1993, The Journal of clinical investigation.

[32]  L. Tessitore,et al.  Humoral mediation for cachexia in tumour-bearing rats. , 1993, British Journal of Cancer.

[33]  M. Siimes,et al.  Tumor necrosis factor in children with malignancies. , 1990, Cancer research.

[34]  J. Tavernier,et al.  EVIDENCE FOR TUMOUR NECROSIS FACTOR/CACHECTIN PRODUCTION IN CANCER , 1987, The Lancet.

[35]  J. Kay,et al.  Multicatalytic proteinase activity in skeletal muscle from starving rat , 1987 .

[36]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[37]  W. Mitch,et al.  Metabolic acidosis stimulates protein degradation in rat muscle by a glucocorticoid-dependent mechanism. , 1986, The Journal of clinical investigation.

[38]  Oliver H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.

[39]  Koji Yamada,et al.  Modulation of body fat and serum leptin levels by dietary conjugated linoleic acid in Sprague-Dawley rats fed various fat-level diets. , 2003, Nutrition.

[40]  J. Wang,et al.  Burn injury upregulates the activity and gene expression of the 20 S proteasome in rat skeletal muscle. , 2000, Clinical science.

[41]  N. Carbó,et al.  Tumor growth and nitrogen metabolism in the host , 1999 .

[42]  G. Tiao,et al.  Sepsis-induced increase in muscle proteolysis is blocked by specific proteasome inhibitors. , 1998, The American journal of physiology.