F-BOX proteins in cancer cachexia and muscle wasting: Emerging regulators and therapeutic opportunities

Sukari, Ammar; Muqbil, Irfana; Mohammad, Ramzi M.; Philip, Philip A.; Azmi, Asfar S.

doi:10.1016/j.semcancer.2016.01.002

Cited by 32 publications

(26 citation statements)

References 113 publications

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“…We found a significant reduction in protein synthesis rates in ventricular tissue. Since tissue protein is also broken down through proteolysis following ubiquitination, we also measured the mRNA transcript levels of the E3 ubiquitin ligases, RING-finger protein-1 (MuRF1)[59] and F-box only protein 32 (FBXO32) protein[60–63] by whole transcriptome shotgun sequencing (WTSS or RNA-seq). We found minor increases in the mRNA levels of these ubiquitin ligases in heart muscle from tumor-bearing mice.…”

Section: Discussionmentioning

confidence: 99%

Impaired cardiac performance, protein synthesis, and mitochondrial function in tumor-bearing mice

et al. 2019

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BackgroundTo understand the underlying mechanisms of cardiac dysfunction in cancer, we examined cardiac function, protein synthesis, mitochondrial function and gene expression in a model of heart failure in mice injected with Lewis lung carcinoma (LLC1) cells.Experimental designSeven week-old C57BL/J6 male and female mice were injected with LLC1 cells or vehicle. Cardiac ejection fraction, ventricular wall and septal thickness were reduced in male, but not female, tumor-bearing mice compared to vehicle-injected control mice. Cardiac protein synthesis was reduced in tumor-bearing male mice compared to control mice (p = 0.025). Aspect ratio and form factor of cardiac mitochondria from the tumor-bearing mice were increased compared control mice (p = 0.042 and p = 0.0032, respectively) indicating a more fused mitochondrial network in the hearts of tumor-bearing mice. In cultured cardiomyocytes maximal oxygen consumption and mitochondrial reserve capacity were reduced in cells exposed to tumor cell-conditioned medium compared to non-conditioned medium (p = 0.0059, p = 0.0010). Whole transcriptome sequencing of cardiac ventricular muscle from tumor-bearing vs. control mice showed altered expression of 1648 RNA transcripts with a false discovery rate of less than 0.05. Of these, 54 RNA transcripts were reduced ≤ 0.5 fold, and 3 RNA transcripts were increased by ≥1.5-fold in tumor-bearing mouse heart compared to control. Notably, the expression of mRNAs for apelin (Apln), the apelin receptor (Aplnr), the N-myc proto-oncogene, early growth protein (Egr1), and the transcription factor Sox9 were reduced by >50%, whereas the mRNA for growth arrest and DNA-damage-inducible, beta (Gadd45b) is increased >2-fold, in ventricular tissue from tumor-bearing mice compared to control mice.ConclusionsLung tumor cells induce heart failure in male mice in association with reduced protein synthesis, mitochondrial function, and the expression of the mRNAs for inotropic and growth factors. These data provide new mechanistic insights into cancer-associated heart failure that may help unlock treatment options for this condition.

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Section: Discussionmentioning

confidence: 99%

Impaired cardiac performance, protein synthesis, and mitochondrial function in tumor-bearing mice

et al. 2019

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“…It is acknowledged that activation of protein degradation and defection of skeletal muscle regeneration induce muscle atrophy. The activation of the ubiquitin ligase family members Atrogin1 (MAFBx/FBX32) and muscle RING finger protein 1 (MuRF1) induce protein degradation and plays an important role in muscle wasting ( Bodine and Baehr, 2014 ; Sukari et al, 2016 ). Simultaneously, the expression of myogenic factors, such as MyHC, MyoG, and MyoD, is downregulated, while that of negative myogenic factors, such as myostatin, is upregulated ( Cohen et al, 2015 ; Bossola et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Linalool Prevents Cisplatin Induced Muscle Atrophy by Regulating IGF-1/Akt/FoxO Pathway

Zhang¹,

Chi

Chen

et al. 2020

Front. Pharmacol.

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Skeletal muscle atrophy is an important feature of cancer cachexia, which can be induced by chemotherapy, and affects the survival and quality of life of cancer patients seriously. No specific drugs for cancer cachexia have been applied in clinical practice. This study explored the therapeutic effect of linalool (LIN) on cisplatin (DDP) induced skeletal muscle atrophy. In vivo, LIN can improve skeletal muscle weight loss, anorexia, muscle strength decline and other cachexia symptoms caused by cisplatin treatment in a Lewis lung cancer tumor bearing mouse model, and cause no adverse effects on the anti-tumour effect. LIN treatment decreased the expression of muscle RING-finger protein-1 (MuRF1) and Atrogin1(MAFbx) in muscle, and the activation of insulin-like growth factor-1 (IGF-1)/protein kinase B (Akt)/forkhead box O (FoxO) pathway was observed. In vitro, LIN alleviated DDP induced C2C12 myotube atrophy, and IGF-1 receptor inhibitor Picropodophyllin (PIC), which had no adverse effect on C2C12 myotube cells, could reverse the protective effect of LIN. These results indicate that LIN down-regulates the expression of Atrogin1 and MuRF1 through the IGF-1/Akt/FoxO pathway, alleviating DDP-induced muscle atrophy and improving cachexia symptoms. LIN has the potential to be developed as a drug against cancer cachexia.

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“…A predicted target at 8q24.13 is FBXO32 , which is expressed in ER-negative human mammary epithelial cells (HMECs) but not ER-positive MCF7 breast cancer cells (Supplementary Fig. 7) and has a known role in cancer cachexia 54 . At 11q22.3 (Fig.…”

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confidence: 99%

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

Milne¹,

Kuchenbaecker²,

Michailidou³

et al. 2017

Nat Genet

317

332

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Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease1. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10−8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 14% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

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F-BOX proteins in cancer cachexia and muscle wasting: Emerging regulators and therapeutic opportunities

Cited by 32 publications

References 113 publications

Impaired cardiac performance, protein synthesis, and mitochondrial function in tumor-bearing mice

Impaired cardiac performance, protein synthesis, and mitochondrial function in tumor-bearing mice

Linalool Prevents Cisplatin Induced Muscle Atrophy by Regulating IGF-1/Akt/FoxO Pathway

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

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