Expression of NF-kappaB and IkappaB proteins in skeletal muscle of gastric cancer patients.
The mechanisms eliciting cancer cachexia are not well understood. Wasting of skeletal muscle is problematic because it is responsible for the clinical deterioration in cancer patients and for the ability to tolerate cancer treatment. Studies done on animals suggest that nuclear factor of kappa B (NF-kappaB) signalling is important in the progression of muscle wasting due to several types of tumours. However, there are no published studies in humans on the role of NF-kappaB in cancer cachexia. In this project, we studied the rectus abdominis muscle in patients with gastric tumours (n=14) and in age-matched control subjects (n=10) for markers of NF-kappaB activation. Nuclear levels of p65, p50 and Bcl-3 were the same in both groups of subjects. However, phospho-p65 was elevated by 25% in the muscles of cancer patients. In addition, expression of the inhibitor of kappa B alpha (IkappaBalpha) was decreased by 25% in cancer patients. Decreased expression of IkappaBalpha reflects its degradation by one of the IkappaBalpha kinases and is a marker of NF-kappaB activation. Interestingly, there was no correlation between the stage of cancer and the extent of IkappaBalpha decrease, nor was there a correlation between the degree of cachexia and decreased IkappaBalpha levels. This suggests that the activation of NF-kappaB is an early and sustained event in gastric cancer. The work implicates the NF-kappaB signalling in the initiation and progression of cancer cachexia in humans and demonstrates the need for additional study of this pathway; it also recommends NF-kappaB signalling as a therapeutic target for the amelioration of cachexia as has been suggested from studies done on rodents.
Department of Health Sciences, Boston University, Boston, MA, USA.
Mary G
MG
Rhoads
Susan C
SC
Kandarian
Fabio
F
Pacelli
Giovan Battista
GB
Doglietto
Maurizio
M
Bossola
D000368:Aged; D000081242:B-Cell Lymphoma 3 Protein; D002100:Cachexia / Q000209:etiology / Q000378:metabolism; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000378:metabolism; D015596:Nutrition Assessment; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism
D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D000072000:NF-KappaB Inhibitor alpha