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Cachexia Signaling— a Targeted Approach to Cancer Treatment Yuji Miyamoto1, Diana L

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Cachexia Signaling— a Targeted Approach to Cancer Treatment Yuji Miyamoto1, Diana L Published OnlineFirst June 23, 2016; DOI: 10.1158/1078-0432.CCR-16-0495 Molecular Pathways Clinical Cancer Research Molecular Pathways: Cachexia Signaling— A Targeted Approach to Cancer Treatment Yuji Miyamoto1, Diana L. Hanna1, Wu Zhang1, Hideo Baba2, and Heinz-Josef Lenz1 Abstract Cancer cachexia is a multifactorial syndrome characterized clinical and clinical studies have demonstrated that anti- by an ongoing loss of skeletal muscle mass, which negatively cachexia drugs (such as MABp1 and soluble receptor antag- affects quality of life and portends a poor prognosis. Numer- onist of myostatin/activin) not only prevent muscle wasting ous molecular substrates and mechanisms underlie the dys- but also may prolong overall survival. In this review, we focus regulation of skeletal muscle synthesis and degradation on the significance of cachexia signaling in patients with observed in cancer cachexia, including proinflammatory cancer and highlight promising drugs targeting tumor cachex- cytokines (TNFa,IL1,andIL6),andtheNF-kB, IGF1/AKT/ ia in clinical development. Clin Cancer Res; 22(16); 3999–4004. mTOR, and myostatin/activin–SMAD pathways. Recent pre- Ó2016 AACR. Background to the development of promising therapies for the prevention of muscle wasting (7). However, advances in this field have been Cancer cachexia is a complex metabolic syndrome charac- impeded by a lack of consensus regarding the clinical assessment terized by an irreversible loss of skeletal muscle mass, which of cancer cachexia as well as the heterogeneity of disease presen- leads to progressive functional impairment (1). Cachexia is a tation (8). A better understanding of the molecular mechanisms significant cause of morbidity and mortality, affecting 60% to underlying tumor cachexia has the potential to identify novel 80% of patients with cancer, and is particularly common in therapeutic targets and inform the development of successful individuals with pancreatic cancer (2, 3). In addition to func- interventions. In this review, we critically summarize cachexia tional impairment, cachexia is associated with increased fatigue signaling in patients with cancer and highlight recent preclinical and emotional distress, all of which considerably compromise and clinical advances in the management of this paraneoplastic quality of life. Moreover, patients with cancer with cachexia are syndrome. less likely to respond to chemotherapy and radiation and are more likely to endure treatment toxicities (4). Importantly, cachexia may be a direct result of malignancy as well as the Cachexia pathways in muscle tissue chemotherapeutics (e.g., bevacizumab or sorafenib) used to Cancer cachexia ultimately results from an imbalance in the treat it. Sarcopenia, a related but distinct condition, also results regulation of muscle protein synthesis and degradation. Such in loss of muscle mass but is attributable to aging and inac- muscle wasting is orchestrated by extracellular ligands which tivity, rather than anorexia, a feature of cachexia marked by activate several intersecting intracellular signaling pathways fl decreased energy expenditure and reduced fat accumulation (Fig. 1). In particular, proin ammatory cytokines derived from a (5). The definition of cachexia has evolved in recent years (1), immune or tumor cells, including TNF , IL1, and IL6, have been k and much remains to be understood regarding the interplay shown to trigger muscle wasting through activation of NF- B and between cachexia, anorexia, and sarcopenia and how these JAK/STAT pathways, respectively. Accumulating evidence also entities affect cancer development, treatment resistance, and suggests that the IGF1 pathway induces skeletal myogenesis, while patient outcomes. myostatin and activin serve as negative regulators of IGF1 signal- Studies evaluating the metabolic alterations inducing cancer ing to inhibit muscle growth and promote degradation. Other cachexia have revealed several tumor-derived cytokines and path- major skeletal muscle proteolytic pathways include the ubiquitin/ ways implicated in skeletal muscle degradation (6) and have led proteasome system (UPS), as well as the autophagy/lysosomal, calpain, and the caspase pathways (9–11). The UPS has received the most attention, through which the ubiquitin E3 ligases, 1Division of Medical Oncology, Norris Comprehensive Cancer Center, muscle ring finger protein 1 (MuRF-1), and atrophy gene Keck School of Medicine, University of Southern California, Los 1/muscle atrophy F-box (Atrogin-1/MAFbx), act as the two main Angeles, California. 2Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kuma- regulators of muscle protein breakdown. moto, Japan. Corresponding Author: Heinz-Josef Lenz, Division of Medical Oncology, Sharon Cytokines activate protein degradation in cancer cachexia Carpenter Laboratory, Norris Comprehensive Cancer Center, Keck School of Multiple cytokines, including TNFa, IL1, and IL6, have been Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, implicated in facilitating a cachectic state (12), and their expres- CA 90033. Phone: 323-865-3967; Fax: 323-865-0061; E-mail: [email protected] sion or upregulation is prompted by both tumor- and host- doi: 10.1158/1078-0432.CCR-16-0495 derived factors. High serum levels of these cytokines are present Ó2016 American Association for Cancer Research. in many patients with cancer with cachexia. www.aacrjournals.org 3999 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst June 23, 2016; DOI: 10.1158/1078-0432.CCR-16-0495 Miyamoto et al. Clazakizumab Etanercept MABp1 Infliximab IGF1 INHBA MSTN IL6 TNFα IL1a LY2495655 TNFαR Bimagrumab IGF1R gp130 IL1R IL6R Type I receptor Type II receptor IRS1 ActRIB (ALK4) ActRIIA JAK TGFBR1 (ALK5) ActRIIB ActRIC (ALK7) IKK complex PI3K SMAD2/3 SMAD4 STAT IkBa AKT p50 RelA U U U mTORC1 FOXO3 U IkBa NF-kB SMAD2/3 STAT GBL mTOR SMAD4 STAT p50 RelA Raptor FOXO3 p70S6K elF4G Atrogin1 Apoptosis Autophagy Protein synthesis MuRF1 LC3-II E3 ligase Atg5-Atg12 Ubiquitination Muscle wasting and Muscle growth Protein degradation cachexia © 2016 American Association for Cancer Research Figure 1. Cachexia signaling regulating protein synthesis and degradation in muscle and anti-cachexia drugs in development. IGF1/Akt/mTOR signaling: Binding of IGF1 to IGF1R results in phosphorylation of the insulin receptor substrate (IRS). IRS activates PI3K/Akt signaling, which then stimulates protein synthesis by activating mTOR. mTOR activates the ribosomal S6K and eukaryotic initiation factor 4E-BP-1, leading to protein synthesis. Akt also phosphorylates and inhibits FoxOs, which is a negative regulator of myogenesis. Myostatin/activin signaling: Myostatin/activin binds to type II receptor (ActRIIB) and induces its dimerization with the activin type I receptor. Subsequent phosphorylation of Smad2/3 recruits Smad4. The Smad complex is translocated into the nucleus to induce transcriptional changes, which result in muscle wasting. Simultaneously, myostatin/activin reduces Akt activity and suppressesFoxOs phosphorylation. Dephosphorylated FoxOs are translocated into the nucleus and induce the transcription of target genes, which regulate the ubiquitin/ proteasome and autophagy/lysosome systems. IL6 signaling: The binding of IL6 to its receptors induces homodimerization of gp130 and its complex, which activate JAK/STAT3 signaling. Phosphorylated STAT3 forms a dimer and translocates into the nucleus, leading to increased protein degradation. TNFa and IL1 signaling: Binding of TNFa or IL1 to its receptor activates the IKK complex, which phosphorylates IkBa proteins. This signal-induced phosphorylation targets IkBa for polyubiquitination and subsequent degradation by the proteasome, thereby allowing the RelB/p52 complex to translocate to the nucleus to transcribe respective target genes. 4000 Clin Cancer Res; 22(16) August 15, 2016 Clinical Cancer Research Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst June 23, 2016; DOI: 10.1158/1078-0432.CCR-16-0495 A Targeted Approach to Cancer Treatment TNFa has long been recognized as a mediator of cancer cachex- protein synthesis by blocking the repression of mTOR. Activated ia. Its administration leads to increased protein degradation in mTOR phosphorylates its two major targets, S6K1 and 4E-BP1, cultured muscle cells (13) and in rat muscle (14). In murine which play a key role in myogenesis. Akt further phosphorylates models, TNFa and recombinant IL1 act synergistically to reduce and inactivates forkhead box O proteins (FoxOs: FoxO1, FoxO3 muscle protein content (15). Mechanistically, these cytokines and FoxO4) by promoting their export from the nucleus to increase NF-kB–mediated transcription and subsequent ubiqui- the cytoplasm (28). FoxOs are transcriptional regulators of tin conjugation activity (16), thereby inducing skeletal muscle autophagy, which promote protein ubiquitination and degra- protein loss. The NF-kB protein family is composed of five dation in muscle cells. Myostatin and activin suppress Akt transcription factors [p65 (Rel A), Rel B, c-Rel, p52, and p50], activity, leading to disinhibition of FoxO3 (29, 30) and subse- which are expressed in skeletal muscle and mediate a variety of quent upregulation of MuRF-1, Atrogin-1 (or MAFbx), and processes depending on the cell type and upstream trigger (17).
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