Cachexia in Cancer — Zeroing in on Myosin
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《新英格兰医药杂志》
Cachexia is a condition associated with a variety of serious diseases, including cancer, AIDS, and congestive heart failure. It is manifested as weight loss involving both adipose tissue and skeletal muscle. Wasting is not due to malnutrition, which preferentially depletes lipids from adipose tissue, but involves a complex disruption of several systems that also leads to anemia, insulin resistance, immunosuppression, and activation of an acute-phase response. The resulting progressive weakness can make patients with cancer more susceptible to the toxic effects of radiation and chemotherapy; many such patients die from cachexia-related syndromes, rather than from their tumors. Knowledge of the mechanisms underlying cachectic effects in muscle and other organs could make possible the development of drugs to counter muscle wasting and maintain strength, thereby increasing patients' resistance to the adverse effects of chemotherapy and radiation. In this regard, a recent study by Acharyya and colleagues represents an advance.1
The molecular pathways that lead to cachexia remain unclear. Various lines of evidence point to factors released both by tumor cells and by immune effector cells responding to the tumors. Early work focused on the release of toxic substances from tumors, known as toxohormones, which appear to be small, proteolytically derived peptides.2 More recent studies have increasingly focused on inflammatory cytokines such as tumor necrosis factor (TNF-), interleukin-1, interleukin-6, and interferon-. Although none of these compounds induce dramatic cachexia-like effects by themselves, in combination they can promote muscle wasting. Why do these cytokines exert such a dramatic effect, and what mechanisms lead to muscle wasting? Acharyya et al.1 report that a major effect of cytokines is the selective targeting of myosin in skeletal muscle.
These authors initially studied the production of contractile proteins in myogenic cell cultures treated with a combination of TNF- and interferon-. They observed that, among myofibrillar proteins, the myosin heavy chain was selectively and progressively depleted at both the protein and the messenger RNA (mRNA) level, suggesting a block at the level of gene transcription. Transcription of the myosin heavy-chain gene and many other muscle genes is regulated in part by the nuclear transcription factor MyoD, and Acharyya and colleagues1 also detected a decrease in MyoD in cultured myotubes treated with TNF- and interferon-. These results imply that TNF- and interferon- selectively trigger a reduction in the expression of the myosin heavy chain through a MyoD-mediated block in gene transcription (Figure 1). Consistent with this interpretation is the finding that the implantation of cells expressing both TNF- and interferon- into muscles of mice led to a similar, specific reduction in the synthesis of the myosin heavy chain relative to that of other myofibrillar proteins, such as actin and tropomyosin.1
Figure 1. The Importance of Myosin in Cachexia.
A recent study by Acharyya and colleagues1 shows that soluble factors released from tumors or immune effector cells and implicated in cachexia can lead to a specific decrease in the levels of the myosin heavy chain, a muscle contractile protein. The data provide support for the existence of two pathways. In Panel A, the combination of tumor necrosis factor (TNF-) and interferon- (IFN-) results in the suppression of the nuclear transcription factor MyoD and, hence, a decrease in the transcription of the myosin heavy chain; a deficit in the cellular pool of myosin heavy chain results in cachexia. Cytokines such as interleukin-6 increase the production of ubiquitin and E3 ubiquitin ligase proteins. In Panel B, stimulation of the ubiquitin ligase–dependent proteasome pathway leads to increased and preferential ubiquination of the myosin heavy chain, causing the dissociation of myosin from the contractile apparatus and its subsequent degradation into peptides by the proteasomes. The loss of functional contractile units, probably combined with the selective loss of other specific proteins, leads to muscle atrophy and wasting.
To extend these studies to a cancer model, Acharyya and colleagues1 studied myofibrillar proteins in mice implanted with cells derived from a human colon tumor, known as colon-26 tumor cells. Although cachexia in this model is primarily associated with the release of interleukin-6, the authors again observed a striking reduction in skeletal-muscle myosin. But the colon-26 mouse model showed no depletion of myosin mRNA levels. Rather, it seems that myosin was selectively degraded as a result of increased activation of the ubiquitin ligase–dependent proteasome pathway, which helps regulate the turnover of proteins and the induction of atrophy in skeletal muscle (Figure 1B).1,3
Thus, multiple cytokines can initiate muscle wasting by selectively targeting myosin. Preferential loss of the myosin heavy-chain protein relative to actin, tropomyosin, and troponin would alter the ratio between thick and thin filaments, probably inducing muscle atrophy in an effort to restore the stoichiometric balance needed to form a functional contractile lattice in myofibrils.
These results suggest that specific proteins are targeted by cachectic factors, implying that selective blockade or enhancement of key signaling pathways could preserve muscle strength in patients susceptible to cachexia. It will be important to analyze a wider range of muscle proteins, since MyoD regulates numerous genes and ubiquitin-linked pathways target many different proteins for degradation.3,4 The initial signaling pathways affected by cachectic factors should also be identified. Does the loss of myosin trigger catabolic effects in muscle, or is it secondarily involved? In either case, identifying the relevant pathways may lead to the development of drugs that could block or counteract the aberrant signaling of these pathways. Even in the absence of a cure for cancer, preventing or ameliorating cachectic muscle wasting could increase both the quality and the length of life in patients with cancer.
Source Information
From the Departments of Neurology, Medicine, and Biochemistry and the Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Washington School of Medicine, Seattle.
References
Acharyya S, Ladner KJ, Nelsen LL, et al. Cancer cachexia is regulated by selective targeting of skeletal muscle gene products. J Clin Invest 2004;114:370-378.
Rubin H. Cancer cachexia: its correlations and causes. Proc Natl Acad Sci U S A 2003;100:5384-5389.
Sandri M, Sandri C, Gilbert A, et al. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 2004;117:399-412.
Bergstrom DA, Penn BH, Strand A, Perry RL, Rudnicki MA, Tapscott SJ. Promoter-specific regulation of MyoD binding and signal transduction cooperate to pattern gene expression. Mol Cell 2002;9:587-600.(Jeffrey S. Chamberlain, P)
The molecular pathways that lead to cachexia remain unclear. Various lines of evidence point to factors released both by tumor cells and by immune effector cells responding to the tumors. Early work focused on the release of toxic substances from tumors, known as toxohormones, which appear to be small, proteolytically derived peptides.2 More recent studies have increasingly focused on inflammatory cytokines such as tumor necrosis factor (TNF-), interleukin-1, interleukin-6, and interferon-. Although none of these compounds induce dramatic cachexia-like effects by themselves, in combination they can promote muscle wasting. Why do these cytokines exert such a dramatic effect, and what mechanisms lead to muscle wasting? Acharyya et al.1 report that a major effect of cytokines is the selective targeting of myosin in skeletal muscle.
These authors initially studied the production of contractile proteins in myogenic cell cultures treated with a combination of TNF- and interferon-. They observed that, among myofibrillar proteins, the myosin heavy chain was selectively and progressively depleted at both the protein and the messenger RNA (mRNA) level, suggesting a block at the level of gene transcription. Transcription of the myosin heavy-chain gene and many other muscle genes is regulated in part by the nuclear transcription factor MyoD, and Acharyya and colleagues1 also detected a decrease in MyoD in cultured myotubes treated with TNF- and interferon-. These results imply that TNF- and interferon- selectively trigger a reduction in the expression of the myosin heavy chain through a MyoD-mediated block in gene transcription (Figure 1). Consistent with this interpretation is the finding that the implantation of cells expressing both TNF- and interferon- into muscles of mice led to a similar, specific reduction in the synthesis of the myosin heavy chain relative to that of other myofibrillar proteins, such as actin and tropomyosin.1
Figure 1. The Importance of Myosin in Cachexia.
A recent study by Acharyya and colleagues1 shows that soluble factors released from tumors or immune effector cells and implicated in cachexia can lead to a specific decrease in the levels of the myosin heavy chain, a muscle contractile protein. The data provide support for the existence of two pathways. In Panel A, the combination of tumor necrosis factor (TNF-) and interferon- (IFN-) results in the suppression of the nuclear transcription factor MyoD and, hence, a decrease in the transcription of the myosin heavy chain; a deficit in the cellular pool of myosin heavy chain results in cachexia. Cytokines such as interleukin-6 increase the production of ubiquitin and E3 ubiquitin ligase proteins. In Panel B, stimulation of the ubiquitin ligase–dependent proteasome pathway leads to increased and preferential ubiquination of the myosin heavy chain, causing the dissociation of myosin from the contractile apparatus and its subsequent degradation into peptides by the proteasomes. The loss of functional contractile units, probably combined with the selective loss of other specific proteins, leads to muscle atrophy and wasting.
To extend these studies to a cancer model, Acharyya and colleagues1 studied myofibrillar proteins in mice implanted with cells derived from a human colon tumor, known as colon-26 tumor cells. Although cachexia in this model is primarily associated with the release of interleukin-6, the authors again observed a striking reduction in skeletal-muscle myosin. But the colon-26 mouse model showed no depletion of myosin mRNA levels. Rather, it seems that myosin was selectively degraded as a result of increased activation of the ubiquitin ligase–dependent proteasome pathway, which helps regulate the turnover of proteins and the induction of atrophy in skeletal muscle (Figure 1B).1,3
Thus, multiple cytokines can initiate muscle wasting by selectively targeting myosin. Preferential loss of the myosin heavy-chain protein relative to actin, tropomyosin, and troponin would alter the ratio between thick and thin filaments, probably inducing muscle atrophy in an effort to restore the stoichiometric balance needed to form a functional contractile lattice in myofibrils.
These results suggest that specific proteins are targeted by cachectic factors, implying that selective blockade or enhancement of key signaling pathways could preserve muscle strength in patients susceptible to cachexia. It will be important to analyze a wider range of muscle proteins, since MyoD regulates numerous genes and ubiquitin-linked pathways target many different proteins for degradation.3,4 The initial signaling pathways affected by cachectic factors should also be identified. Does the loss of myosin trigger catabolic effects in muscle, or is it secondarily involved? In either case, identifying the relevant pathways may lead to the development of drugs that could block or counteract the aberrant signaling of these pathways. Even in the absence of a cure for cancer, preventing or ameliorating cachectic muscle wasting could increase both the quality and the length of life in patients with cancer.
Source Information
From the Departments of Neurology, Medicine, and Biochemistry and the Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Washington School of Medicine, Seattle.
References
Acharyya S, Ladner KJ, Nelsen LL, et al. Cancer cachexia is regulated by selective targeting of skeletal muscle gene products. J Clin Invest 2004;114:370-378.
Rubin H. Cancer cachexia: its correlations and causes. Proc Natl Acad Sci U S A 2003;100:5384-5389.
Sandri M, Sandri C, Gilbert A, et al. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 2004;117:399-412.
Bergstrom DA, Penn BH, Strand A, Perry RL, Rudnicki MA, Tapscott SJ. Promoter-specific regulation of MyoD binding and signal transduction cooperate to pattern gene expression. Mol Cell 2002;9:587-600.(Jeffrey S. Chamberlain, P)