bims-aucach 2022-01-16 papers

bims-aucach

Biomed News

on Autophagy and cachexia

Issue of 2022‒01‒16
ten papers selected by
Kleiton Silva
Rowan University

Physical exercise at the crossroad between muscle wasting and the immune system: implications for lung cancer cachexia.
C/EBPβ promotes the expression of atrophy-inducing factors by tumours and is a central regulator of cancer cachexia.
Aerobic Exercise Training and In Vivo Akt Activation Counteract Cancer Cachexia by Inducing a Hypertrophic Profile through eIF-2α Modulation.
Aging Aggravates Cachexia in Tumor-Bearing Mice.
Primary skeletal muscle cells from chronic kidney disease patients retain hallmarks of cachexia in vitro.
Synergistic effects of autophagy/mitophagy inhibitors and magnolol promote apoptosis and antitumor efficacy.
The Role of Altered Mitochondrial Metabolism in Thyroid Cancer Development and Mitochondria-Targeted Thyroid Cancer Treatment.
The complex interplay between autophagy and cell death pathways.
Autophagy inhibits cancer stemness in triple-negative breast cancer via miR-181a-mediated regulation of ATG5 and/or ATG2B.
Validation of the functional assessment of anorexia/cachexia therapy instrument to assess quality of life in maintenance hemodialysis patients with cachexia.

J Cachexia Sarcopenia Muscle. 2022 Jan 10.

Physical exercise at the crossroad between muscle wasting and the immune system: implications for lung cancer cachexia.

Francesco Cortiula, Lizza E L Hendriks, Wouter R P H van de Worp, Annemie M W J Schols, Rianne D W Vaes, Ramon C J Langen, Dirk De Ruysscher.

  Cachexia is a syndrome characterized by involuntary weight loss and wasting of skeletal muscle mass. It is associated with worse overall survival and quality of life. The cancer-induced systemic inflammation and the consequent host derived catabolic stimuli, trigger cachexia by inhibiting muscle protein synthesis and enhancing muscle catabolism. The muscle itself may further promote chronic inflammation, introducing a vicious catabolic circle. Nutritional support alone plays a limited role in the treatment of cancer cachexia and should be combined with other interventions. Physical exercise lowers systemic inflammation and promotes muscle anabolism. It also attenuates the age-related physical decline in elderly and it might counteract the muscle wasting induced by the cancer cachexia syndrome. This review describes how cancer-induced systemic inflammation promotes muscle wasting and whether physical exercise may represent a suitable treatment for cancer-induced cachexia, particularly in patients with non-small cell lung cancer. We summarized pre-clinical and clinical studies investigating whether physical exercise would improve muscle performance and whether this improvement would translate in a clinically meaningful benefit for patients with cancer, in terms of survival and quality of life. Moreover, this review describes the results of studies investigating the interplay between physical exercise and the immune system, including the role of the intestinal microbiota.

Keywords:  Cachexia; Gut microbiota; Immune system; Physical exercise; Systemic inflammation

DOI:  https://doi.org/10.1002/jcsm.12900
J Cachexia Sarcopenia Muscle. 2022 Jan 10.

C/EBPβ promotes the expression of atrophy-inducing factors by tumours and is a central regulator of cancer cachexia.

Hamood AlSudais, Rashida Rajgara, Aisha Saleh, Nadine Wiper-Bergeron.

  BACKGROUND: CCAAT/enhancer-binding protein β (C/EBPβ) is a transcription factor whose high expression in human cancers is associated with tumour aggressiveness and poor outcomes. Most advanced cancer patients will develop cachexia, characterized by loss of skeletal muscle mass. In response to secreted factors from cachexia-inducing tumours, C/EBPβ is stimulated in muscle, leading to both myofibre atrophy and the inhibition of muscle regeneration. Involved in the regulation of immune responses, C/EBPβ induces the expression of many secreted factors, including cytokines. Because tumour-secreted factors drive cachexia and aggressive tumours have higher expression of C/EBPβ, we examined a potential role for C/EBPβ in the expression of tumour-derived cachexia-inducing factors.METHODS: We used gain-of-function and loss-of-function approaches in vitro and in vivo to evaluate the role of tumour C/EBPβ expression on the secretion of cachexia-inducing factors.
RESULTS: We report that C/EBPβ overexpression up-regulates the expression of 260 secreted protein genes, resulting in a secretome that inhibits myogenic differentiation (-31%, P < 0.05) and myotube maturation [-38% (fusion index) and -25% (myotube diameter), P < 0.05]. We find that knockdown of C/EBPβ in cachexia-inducing Lewis lung carcinoma cells restores myogenic differentiation (+25%, P < 0.0001) and myotube diameter (+90%, P < 0.0001) in conditioned medium experiments and, in vivo, prevents muscle wasting (-51% for small myofibres vs. controls, P < 0.01; +140% for large myofibres, P < 0.01). Conversely, overexpression of C/EBPβ in non-cachectic tumours converts their secretome into a cachexia-inducing one, resulting in reduced myotube diameter (-41%, P < 0.0001, EL4 model) and inhibition of differentiation in culture (-26%, P < 0.01, EL4 model) and muscle wasting in vivo (+98% small fibres, P < 0.001; -76% large fibres, P < 0.001). Comparison of the differently expressed transcripts coding for secreted proteins in C/EBPβ-overexpressing myoblasts with the secretome from 27 different types of human cancers revealed ~18% similarity between C/EBPβ-regulated secreted proteins and those secreted by highly cachectic tumours (brain, pancreatic, and stomach cancers). At the protein level, we identified 16 novel secreted factors that are present in human cancer secretomes and are up-regulated by C/EBPβ. Of these, we tested the effect of three factors (SERPINF1, TNFRSF11B, and CD93) on myotubes and found that all had atrophic potential (-33 to -36% for myotube diameter, P < 0.01).
CONCLUSIONS: We find that C/EBPβ is necessary and sufficient to induce the secretion of cachexia-inducing factors by cancer cells and loss of C/EBPβ in tumours attenuates muscle atrophy in an animal model of cancer cachexia. Our findings establish C/EBPβ as a central regulator of cancer cachexia and an important therapeutic target.

Keywords:  CCAAT-enhancer-binding proteins; Cachexia; Carcinoma, Lewis lung; Muscle, skeletal; Muscular atrophy; Secreted proteins

DOI:  https://doi.org/10.1002/jcsm.12909
Cancers (Basel). 2021 Dec 22. pii: 28. [Epub ahead of print]14(1):

Aerobic Exercise Training and In Vivo Akt Activation Counteract Cancer Cachexia by Inducing a Hypertrophic Profile through eIF-2α Modulation.

Marcelo G Pereira, Vanessa A Voltarelli, Gabriel C Tobias, Lara de Souza, Gabriela S Borges, Ailma O Paixão, Ney R de Almeida, Thomas Scott Bowen, Marilene Demasi, Elen H Miyabara, Patricia C Brum.

  Cancer cachexia is a multifactorial and devastating syndrome characterized by severe skeletal muscle mass loss and dysfunction. As cachexia still has neither a cure nor an effective treatment, better understanding of skeletal muscle plasticity in the context of cancer is of great importance. Although aerobic exercise training (AET) has been shown as an important complementary therapy for chronic diseases and associated comorbidities, the impact of AET on skeletal muscle mass maintenance during cancer progression has not been well documented yet. Here, we show that previous AET induced a protective mechanism against tumor-induced muscle wasting by modulating the Akt/mTORC1 signaling and eukaryotic initiation factors, specifically eIF2-α. Thereafter, it was determined whether the in vivo Akt activation would induce a hypertrophic profile in cachectic muscles. As observed for the first time, Akt-induced hypertrophy was able and sufficient to either prevent or revert cancer cachexia by modulating both Akt/mTORC1 pathway and the eIF-2α activation, and induced a better muscle functionality. These findings provide evidence that skeletal muscle tissue still preserves hypertrophic potential to be stimulated by either AET or gene therapy to counteract cancer cachexia.

Keywords:  Akt-induced hypertrophy; Akt/mTORC1 signaling; cancer cachexia; eIF-2α; physical exercise; skeletal muscle plasticity; translation initiation

DOI:  https://doi.org/10.3390/cancers14010028
Cancers (Basel). 2021 Dec 24. pii: 90. [Epub ahead of print]14(1):

Aging Aggravates Cachexia in Tumor-Bearing Mice.

Julia Geppert, Alina A Walth, Raúl Terrón Expósito, Doris Kaltenecker, Pauline Morigny, Juliano Machado, Maike Becker, Estefania Simoes, Joanna D C C Lima, Carolin Daniel, Mauricio Berriel Diaz, Stephan Herzig, Marilia Seelaender, Maria Rohm.

  BACKGROUND: Cancer is primarily a disease of high age in humans, yet most mouse studies on cancer cachexia are conducted using young adolescent mice. Given that metabolism and muscle function change with age, we hypothesized that aging may affect cachexia progression in mouse models.METHODS: We compare tumor and cachexia development in young and old mice of three different strains (C57BL/6J, C57BL/6N, BALB/c) and with two different tumor cell lines (Lewis Lung Cancer, Colon26). Tumor size, body and organ weights, fiber cross-sectional area, circulating cachexia biomarkers, and molecular markers of muscle atrophy and adipose tissue wasting are shown. We correlate inflammatory markers and body weight dependent on age in patients with cancer.
RESULTS: We note fundamental differences between mouse strains. Aging aggravates weight loss in LLC-injected C57BL/6J mice, drives it in C57BL/6N mice, and does not influence weight loss in C26-injected BALB/c mice. Glucose tolerance is unchanged in cachectic young and old mice. The stress marker GDF15 is elevated in cachectic BALB/c mice independent of age and increased in old C57BL/6N and J mice. Inflammatory markers correlate significantly with weight loss only in young mice and patients.
CONCLUSIONS: Aging affects cachexia development and progression in mice in a strain-dependent manner and influences the inflammatory profile in both mice and patients. Age is an important factor to consider for future cachexia studies.

Keywords:  aging; cachexia; cancer; mouse models

DOI:  https://doi.org/10.3390/cancers14010090
J Cachexia Sarcopenia Muscle. 2022 Jan 14.

Primary skeletal muscle cells from chronic kidney disease patients retain hallmarks of cachexia in vitro.

Luke A Baker, Thomas F O'Sullivan, Katherine A Robinson, Matthew P M Graham-Brown, Rupert W Major, Robert U Ashford, Alice C Smith, Andrew Philp, Emma L Watson.

  BACKGROUND: Skeletal muscle wasting and dysfunction are common characteristics noted in people who suffer from chronic kidney disease (CKD). The mechanisms by which this occurs are complex, and although progress has been made, the key underpinning mechanisms are not yet fully elucidated. With work to date primarily conducted in nephrectomy-based animal models, translational capacity to our patient population has been challenging. This could be overcome if rationale developing work could be conducted in human based models with greater translational capacity. This could be achieved using cells derived from patient biopsies, if they retain phenotypic traits noted in vivo.METHODS: Here, we performed a systematic characterization of CKD derived muscle cells (CKD; n = 10; age: 54.40 ± 15.53 years; eGFR: 22.25 ± 13.22 ml/min/1.73 m2 ) in comparison with matched controls (CON; n = 10; age: 58.66 ± 14.74 years; eGFR: 85.81 ± 8.09 ml/min/1.73 m2 ). Harvested human derived muscle cells (HDMCs) were taken through proliferative and differentiation phases and investigated in the context of myogenic progression, inflammation, protein synthesis, and protein breakdown. Follow up investigations exposed HDMC myotubes from each donor type to 0, 0.4, and 100 nM of IGF-1 in order to investigate any differences in anabolic resistance.
RESULTS: Harvested human derived muscle cells isolated from CKD patients displayed higher rates of protein degradation (P = 0.044) alongside elevated expression of both TRIM63 (2.28-fold higher, P = 0.054) and fbox32 (6.4-fold higher, P < 0.001) in comparison with CONs. No differences were noted in rates of protein synthesis under basal conditions (P > 0.05); however, CKD derived cells displayed a significant degree of anabolic resistance in response to IGF-1 stimulation (both doses) in comparison with matched CONs (0.4 nm: P < 0.001; 100 nM: P < 0.001).
CONCLUSIONS: In summary, we report for the first time that HDMCs isolated from people suffering from CKD display key hallmarks of the well documented in vivo phenotype. Not only do these findings provide further mechanistic insight into CKD specific cachexia, but they also demonstrate this is a reliable and suitable model in which to perform targeted experiments to begin to develop novel therapeutic strategies targeting the CKD associated decline in skeletal muscle mass and function.

Keywords:  Anabolic resistance; Cachexia; Chronic kidney disease; Protein breakdown; Skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.12802
Acta Pharm Sin B. 2021 Dec;11(12): 3966-3982

Synergistic effects of autophagy/mitophagy inhibitors and magnolol promote apoptosis and antitumor efficacy.

Yancheng Tang, Liming Wang, Tao Yi, Jun Xu, Jigang Wang, Jiang-Jiang Qin, Qilei Chen, Ka-Man Yip, Yihang Pan, Peng Hong, Yingying Lu, Han-Ming Shen, Hu-Biao Chen.

  Mitochondria as a signaling platform play crucial roles in deciding cell fate. Many classic anticancer agents are known to trigger cell death through induction of mitochondrial damage. Mitophagy, one selective autophagy, is the key mitochondrial quality control that effectively removes damaged mitochondria. However, the precise roles of mitophagy in tumorigenesis and anticancer agent treatment remain largely unclear. Here, we examined the functional implication of mitophagy in the anticancer properties of magnolol, a natural product isolated from herbal Magnolia officinalis. First, we found that magnolol induces mitochondrial depolarization, causes excessive mitochondrial fragmentation, and increases mitochondrial reactive oxygen species (mtROS). Second, magnolol induces PTEN-induced putative kinase protein 1 (PINK1)‒Parkin-mediated mitophagy through regulating two positive feedforward amplification loops. Third, magnolol triggers cancer cell death and inhibits neuroblastoma tumor growth via the intrinsic apoptosis pathway. Moreover, magnolol prolongs the survival time of tumor-bearing mice. Finally, inhibition of mitophagy by PINK1/Parkin knockdown or using inhibitors targeting different autophagy/mitophagy stages significantly promotes magnolol-induced cell death and enhances magnolol's anticancer efficacy, both in vitro and in vivo. Altogether, our study demonstrates that magnolol can induce autophagy/mitophagy and apoptosis, whereas blockage of autophagy/mitophagy remarkably enhances the anticancer efficacy of magnolol, suggesting that targeting mitophagy may be a promising strategy to overcome chemoresistance and improve anticancer therapy.

Keywords:  Apoptosis; Combination therapy; Magnolol; PINK1‒Parkin-mediated mitophagy; Tumor suppression

DOI:  https://doi.org/10.1016/j.apsb.2021.06.007
Int J Mol Sci. 2021 Dec 31. pii: 460. [Epub ahead of print]23(1):

The Role of Altered Mitochondrial Metabolism in Thyroid Cancer Development and Mitochondria-Targeted Thyroid Cancer Treatment.

Siarhei A Dabravolski, Nikita G Nikiforov, Alexander D Zhuravlev, Nikolay A Orekhov, Liudmila M Mikhaleva, Alexander N Orekhov.

  Thyroid cancer (TC) is the most common type of endocrine malignancy. Tumour formation, progression, and metastasis greatly depend on the efficacy of mitochondria-primarily, the regulation of mitochondria-mediated apoptosis, Ca2+ homeostasis, dynamics, energy production, and associated reactive oxygen species generation. Recent studies have successfully confirmed the mitochondrial aetiology of thyroid carcinogenesis. In this review, we focus on the recent progress in understanding the molecular mechanisms of thyroid cancer relating to altered mitochondrial metabolism. We also discuss the repurposing of known drugs and the induction of mitochondria-mediated apoptosis as a new trend in the development of anti-TC therapy.

Keywords:  apoptosis; mitochondrial DNA mutation; mitochondrial dynamics; mitophagy; thyroid cancer

DOI:  https://doi.org/10.3390/ijms23010460
Biochem J. 2022 Jan 14. 479(1): 75-90

The complex interplay between autophagy and cell death pathways.

Christina Ploumi, Margarita-Elena Papandreou, Nektarios Tavernarakis.

  Autophagy is a universal cellular homeostatic process, required for the clearance of dysfunctional macromolecules or organelles. This self-digestion mechanism modulates cell survival, either directly by targeting cell death players, or indirectly by maintaining cellular balance and bioenergetics. Nevertheless, under acute or accumulated stress, autophagy can also contribute to promote different modes of cell death, either through highly regulated signalling events, or in a more uncontrolled inflammatory manner. Conversely, apoptotic or necroptotic factors have also been implicated in the regulation of autophagy, while specific factors regulate both processes. Here, we survey both earlier and recent findings, highlighting the intricate interaction of autophagic and cell death pathways. We, Furthermore, discuss paradigms, where this cross-talk is disrupted, in the context of disease.

Keywords:  apoptosis; autophagic cell death; autophagy; cancer; necroptosis; neurodegeneration

DOI:  https://doi.org/10.1042/BCJ20210450
Mol Oncol. 2022 Jan 13.

Autophagy inhibits cancer stemness in triple-negative breast cancer via miR-181a-mediated regulation of ATG5 and/or ATG2B.

Jee Won Park, Yesol Kim, Soo-Been Lee, Chae Won Oh, Eun Ji Lee, Je Yeong Ko, Jong Hoon Park.

  Autophagy has a dual role in the maintenance of cancer stem cells (CSCs), but the precise relationship between autophagy and cancer stemness requires further investigation. In this study, it was found that luminal and triple-negative breast cancers require distinct therapeutic approaches because of their different amounts of autophagy flux. We identified that autophagy flux was inhibited in triple-negative breast cancer (TNBC) CSCs. Moreover, miRNA-181a (miR-181a) expression is upregulated both in TNBC CSCs and patient tissues. Autophagy related 5 (ATG5) and autophagy related 2B (ATG2B) participate in the early formation of autophagosomes and were revealed as targets of miR-181a. Inhibition of miR-181a expression led to attenuation of TNBC stemness and an increase in autophagy flux. Furthermore, treatment with curcumin led to attenuation of cancer stemness in TNBC CSCs; the expression of ATG5 and ATG2B was enhanced and there was an increase of autophagy flux. These results indicated that ATG5 and ATG2B are involved in the suppression of cancer stemness in TNBC. In summary, autophagy inhibits cancer stemness through the miR-181a-regulated mechanism in TNBC. Promoting tumor-suppressive autophagy using curcumin may be a potential method for the treatment of TNBC.

Keywords:  ATG2B; ATG5; autophagy; cancer stemness; miR-181a; triple-negative breast cancer

DOI:  https://doi.org/10.1002/1878-0261.13180
Semin Dial. 2022 Jan 14.

Validation of the functional assessment of anorexia/cachexia therapy instrument to assess quality of life in maintenance hemodialysis patients with cachexia.

Zhen Yang, Yixin Luo, Haizhen Lu, Baolin Zou, Han Wang, Guowei Chen, Yiping Wu, Yanlin Huang.

BACKGROUND: Many patients on maintenance hemodialysis (MHD) eventually suffer from cachexia. The Functional Assessment of Anorexia/Cachexia Therapy (FAACT) is a tool used to evaluate the quality of life of patients with cachexia related to various diseases, but its suitability for use in MHD patients has yet to be verified. This study aimed to explore the validation of the FAACT in MHD patients by conducting reliability and validity tests.METHODS: Qualified MHD patients were selected to complete the FAACT and Kidney Disease Quality of Life Short Form 36 (KDQOL-36) questionnaires, and their demographic data and biochemical test results were collected from electronic medical records. Next, the Cronbach's alpha coefficient, paired sample t test and ICC were used to analyze the scale consistency. Additionally, the association between the KDQOL-36 and FAACT was analyzed using Bland-Altman plots and Pearson correlation analysis. Finally, the patients were divided into groups to evaluate discriminant validity.
RESULTS: A total of 299 patients were included in this study. The Cronbach's alpha coefficients of the FAACT and its anorexia-cachexia subscale (ACS) were 0.904 and 0.842, respectively, and their ICC exceeded 0.90. The correlation coefficients between the FAACT and its items ranged from 0.146 to 0.631, and the correlation coefficients between the FAACT and KDQOL-36 dimensions ranged from 0.446 to 0.617. The Bland-Altman plots between the FAACT and KDQOL-36 showed that only 3.3% of the points were outside the 95% limits of agreement. The effects of cachexia status (present or absent) on FAACT and ACS scores had effect sizes of 0.54 (P < 0.001) and 0.60 (P < 0.001), respectively. The FAACT and ACS also significantly discriminated between patients with and without inflammation (P < 0.001).
CONCLUSIONS: The FAACT and ACS have acceptable reliability and validity in MHD patients and are suitable for measuring the quality of life of MHD patients with cachexia.

DOI: https://doi.org/10.1111/sdi.13053