Inhibition of Stat3 Activation Suppresses Caspase-3 and the Ubiquitin-Proteasome System, Leading to Preservation of Muscle Mass in Cancer Cachexia

Silva, Kleiton Augusto Santos; Dong, Jingfang; Dong, Yanjun; Dong, Yan; Schor, Nestor; Tweardy, David J.; Zhang, Liping; Mitch, William E.

doi:10.1074/jbc.m115.641514

Cited by 182 publications

(250 citation statements)

References 49 publications

(82 reference statements)

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“…This is in agreement with others who have implicated STAT in the transcriptional changes during C26 cancer cachexia (8,12,30), but it is the first time that a STAT transcriptional assay has been used as evidence. Subsequent to the finding that only STAT was activated by C26 CM, we found, remarkably, that LIF is the cytokine stimulating the JAK/STAT pathway in myotubes treated with medium from C26 cancer cells.…”

Section: Discussionsupporting

confidence: 79%

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A Key Role for Leukemia Inhibitory Factor in C26 Cancer Cachexia

Seto

Kandarian

Jackman

2015

Journal of Biological Chemistry

107

113

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Background: Cachexia is the widespread loss of muscle and fat that causes death in many cancers. Results: Secretion of leukemia inhibitory factor (LIF) by C26 cancer cells activates differential gene expression that results in muscle cell atrophy. Conclusion: LIF produced by cancer cells acts on muscle to cause atrophy. Significance: LIF and its signaling pathway are new targets in fighting cancer cachexia.

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Section: Discussionsupporting

confidence: 79%

“…The finding of C/EBP␦ is interesting because it has been linked to C26 cancer cachexia in a recent paper (30). Increased expression of Bnip3 and Casp4 is also suggestive of the activities that could produce atrophy of myotubes by LIF.…”

Section: Discussionmentioning

confidence: 84%

A Key Role for Leukemia Inhibitory Factor in C26 Cancer Cachexia

Seto

Kandarian

Jackman

2015

Journal of Biological Chemistry

107

113

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“…13,25 A signal that initiates muscle wasting is impairment in insulin or IGF-1 signaling pathways that phosphorylate a sequence of proteins, including SGK-1 and Akt. [26][27][28] SGK-1 and Akt are activated by PI3K and mTORC2 phosphorylation at two separate sites (for SGK-1, Ser422 and Thr256 and for Akt, Ser473 and Thr308).…”

Section: Discussionmentioning

confidence: 99%

Serum Glucocorticoid–Regulated Kinase 1 Blocks CKD–Induced Muscle Wasting Via Inactivation of FoxO3a and Smad2/3

Luo

Liang

et al. 2016

JASN

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Muscle proteolysis in CKD is stimulated when the ubiquitin-proteasome system is activated. Serum glucocorticoid-regulated kinase 1 (SGK-1) is involved in skeletal muscle homeostasis, but the role of this protein in CKDinduced muscle wasting is unknown. We found that, compared with muscles from healthy controls, muscles from patients and mice with CKD express low levels of SGK-1. In mice, SGK-1-knockout (SGK-1-KO) induced muscle loss that correlated with increased expression of ubiquitin E3 ligases known to facilitate protein degradation by the ubiquitin-proteasome, and CKD substantially aggravated this response. SGK-1-KO also altered the phosphorylation levels of transcription factors FoxO3a and Smad2/3. In C2C12 muscle cells, expression of dominant negative FoxO3a or knockdown of Smad2/3 suppressed the upregulation of E3 ligases induced by loss of SGK-1. Additionally, SGK-1 overexpression increased the level of phosphorylated N-myc downstreamregulated gene 1 protein, which directly interacted with and suppressed the phosphorylation of Smad2/3. Overexpression of SGK-1 in wild-type mice with CKD had similar effects on the phosphorylation of FoxO3a and Smad2/3 and prevented CKD-induced muscle atrophy. Finally, mechanical stretch of C2C12 muscle cells or treadmill running of wild-type mice with CKD stimulated SGK-1 production, and treadmill running inhibited proteolysis in muscle. These protective responses were absent in SGK-1-KO mice. Thus, SGK-1 could be a mechanical sensor that mediates exercise-induced improvement in muscle wasting stimulated by CKD. 27: 279727: -280827: , 201627: . doi: 10.1681 CKD is frequently complicated by muscle atrophy because of stimulation of muscle protein degradation mediated by increased activity of both caspase-3 and the ubiquitin-proteasome system (UPS). 1 In muscles of rodents with CKD, caspase-3 stimulates cleavage of the complex structure of muscle protein to provide substrates for degradation by the UPS; it also stimulates proteolytic activity of the 26S proteasome. 2 The UPS can selectively degrade myofibrillar protein by stimulating the expression of ubiquitin E3 ligases, Atrogin1 and MuRF1. These ligases conjugate ubiquitin to proteins targeted for protein degradation, resulting in their degradation in the 26S proteasome. 3 Conditions associated with CKD that initiate loss of muscle mass include metabolic acidosis, inflammation, excess angiotensin II, myostatin expression, and insulin resistance. 1 J Am Soc Nephrol

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“…STAT3 is also involved in cancer cachexia by stimulating proteolysis through activation of both the proteasome and apoptosis-related protease caspase 3 in muscle of cancer-bearing animals. 100 In contrast to the proteasome function that is decreased in CSCs, the expression of individual sub-units may be increased. This is the case for sub-unit PSMD10 (Gankyrin) that shows an increased expression in colon CSCs, and its expression correlates with the expression of the stem cell marker CD133.…”

Section: Rbx1mentioning

confidence: 99%

Proteasome expression and activity in cancer and cancer stem cells

Voutsadakis

2017

Tumour Biol.

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Proteasome is a multi-protein organelle that participates in cellular proteostasis by destroying damaged or short-lived proteins in an organized manner guided by the ubiquitination signal. By being in a central place in the cellular protein complement homeostasis, proteasome is involved in virtually all cell processes including decisions on cell survival or death, cell cycle, and differentiation. These processes are important also in cancer, and thus, the proteasome is an important regulator of carcinogenesis. Cancers include a variety of cells which, according to the cancer stem cell theory, descend from a small percentage of cancer stem cells, alternatively termed tumor-initiating cells. These cells constitute the subsets that have the ability to propagate the whole variety of cancer and repopulate tumors after cytostatic therapies. Proteasome plays a role in cellular processes in cancer stem cells, but it has been found to have a decreased function in them compared to the rest of cancer cells. This article will discuss the transcriptional regulation of proteasome sub-unit proteins in cancer and in particular cancer stem cells and the relationship of the proteasome with the pluripotency that is the defining characteristic of stem cells. Therapeutic opportunities that present from the understanding of the proteasome role will also be discussed.

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Inhibition of Stat3 Activation Suppresses Caspase-3 and the Ubiquitin-Proteasome System, Leading to Preservation of Muscle Mass in Cancer Cachexia

Cited by 182 publications

References 49 publications

A Key Role for Leukemia Inhibitory Factor in C26 Cancer Cachexia

A Key Role for Leukemia Inhibitory Factor in C26 Cancer Cachexia

Serum Glucocorticoid–Regulated Kinase 1 Blocks CKD–Induced Muscle Wasting Via Inactivation of FoxO3a and Smad2/3

Proteasome expression and activity in cancer and cancer stem cells

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