Activity of the Akt-dependent anabolic and catabolic pathways in muscle and liver samples in cancer-related cachexia.
In animal models of cachexia, alterations in the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway have been demonstrated in atrophying skeletal muscles. Therefore, we assessed the activity of proteins in this pathway in muscle and liver biopsies from 16 patients undergoing pancreatectomy for suspect of carcinoma. Patients were divided in a non-cachectic or cachectic group according to their weight loss before operation. Extracts of skeletal muscle and liver tissue from eight cachectic patients with pancreas carcinoma and eight non-cachectic patients were analysed by Western blotting using pan- and phospho-specific antibodies directed against eight important signal transduction proteins of the PI3-K/Akt pathway. Muscle samples from cachectic patients revealed significantly decreased levels of myosin heavy chain (-45%) and actin (-18%) in comparison to non-cachectic samples. Akt protein level was decreased by -55%. The abundance and/or phosphorylation of the transcription factors Foxo1 and Foxo3a were reduced by up to fourfold in muscle biopsies from cachectic patients. Various decreases of the phosphorylated forms of the protein kinases mTOR (-82%) and p70S6K (-39%) were found. In contrast to skeletal muscle, cachexia is associated with a significant increase in phosphorylated Akt level in the liver samples with a general activation of the PI3-K/Akt cascade. Our study demonstrates a cachexia-associated loss of Akt-dependent signalling in human skeletal muscle with decreased activity of regulators of protein synthesis and a disinhibition of protein degradation.
Schmitt
Thomas L
TL
Division of Immunochemistry (D020), German Cancer Research Center, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. tlrp.schmitt@web.de
Martignoni
Marcus E
ME
Bachmann
Jeannine
J
Fechtner
Kerstin
K
Friess
Helmut
H
Kinscherf
Ralf
R
Hildebrandt
Wulf
W
D000199:Actins / Q000378:metabolism; D001706:Biopsy; D002100:Cachexia / Q000150:complications* / Q000201:enzymology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D008875:Middle Aged; D009132:Muscles / Q000201:enzymology*; D009218:Myosins / Q000378:metabolism; D009369:Neoplasms / Q000150:complications* / Q000201:enzymology*; D010195:Pancreatitis / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases
D000199:Actins; D051858:Forkhead Transcription Factors; D008840:Microfilament Proteins; D009218:Myosins; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C071058:moesin; C546842:MTOR protein, human