Mechanisms of skeletal muscle degradation and its therapy in cancer cachexia.
Severe or chronic disease can lead to cachexia which involves weight loss and muscle wasting. Cancer cachexia contributes significantly to disease morbidity and mortality. Multiple studies have shown that the metabolic changes that occur with cancer cachexia are unique compared to that of starvation. Specifically, cancer patients seem to lose a larger proportion of skeletal muscle mass. There are three pathways that contribute to muscle protein degradation: the lysosomal system, cytosolic proteases and the ubiquitin (Ub)-proteasome pathway. The Ub-proteasome pathway seems to account for the majority of skeletal muscle degradation in cancer cachexia and is stimulated by several cytokines including tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, interferon-gamma and proteolysis-inducing factor. Cachexia is particularly severe in pancreatic cancer and contributes significantly to the quality of life and mortality of these patients. Several factors contribute to weight loss in these patients, including alimentary obstruction, pain, depression, side effects of therapy and a high catabolic state. Although no single agent has proven to halt cachexia in these patients there has been some progress in the areas of nutrition with supplementation and pharmacological agents such as megesterol acetate, steroids and experimental trials targeting cytokines that stimulate the Ub-proteasome pathway.
Melstrom
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LG
Department of Surgery and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
Melstrom
K A
KA
Ding
X-Z
XZ
Adrian
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TE
D000305:Adrenal Cortex Hormones / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D019167:Appetite Stimulants / Q000494:pharmacology / Q000627:therapeutic use*; D002100:Cachexia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism* / Q000628:therapy; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D019290:Megestrol Acetate / Q000627:therapeutic use; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D018529:Nutritional Support; D010190:Pancreatic Neoplasms / Q000150:complications* / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D000305:Adrenal Cortex Hormones; D019167:Appetite Stimulants; D016207:Cytokines; D009124:Muscle Proteins; D025801:Ubiquitin; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; D019290:Megestrol Acetate