bims-apauto 2021-03-28 papers

bims-apauto

Biomed News

on Apoptosis and autophagy

Issue of 2021‒03‒28
eleven papers selected by
Su Hyun Lee
Seoul National University

Is targeting autophagy mechanism in cancer a good approach? The possible double-edge sword effect.
Inhibition of GSK-3 ameliorates the pathogenesis of Huntington's disease.
Targeting Autophagy in Neurodegenerative Diseases: from Molecular Mechanisms to Clinical Therapeutics.
Autophagy in tumour immunity and therapy.
GRP78 in lung cancer.
Protein phosphatase 6 dissociates the Beclin 1/Vps34 complex and inhibits autophagy.
Autophagy-dependent survival is controlled with a unique regulatory network upon various cellular stress events.
Increased LRRK2 kinase activity alters neuronal autophagy by disrupting the axonal transport of autophagosomes.
The Regulation of ROS- and BECN1-Mediated Autophagy by Human Telomerase Reverse Transcriptase in Glioblastoma.
Parkinson's disease and mitophagy: an emerging role for LRRK2.
The Crosstalk between Autophagy and Apoptosis Is Necessary for Myogenic Differentiation.

Cell Biosci. 2021 Mar 20. 11(1): 56

Is targeting autophagy mechanism in cancer a good approach? The possible double-edge sword effect.

Su Min Lim, Ezanee Azlina Mohamad Hanif, Siok-Fong Chin.

  Autophagy is a conserved cellular process required to maintain homeostasis. The hallmark of autophagy is the formation of a phagophore that engulfs cytosolic materials for degradation and recycling to synthesize essential components. Basal autophagy is constitutively active under normal conditions and it could be further induced by physiological stimuli such as hypoxia, nutrient starvation, endoplasmic reticulum stress,energy depletion, hormonal stimulation and pharmacological treatment. In cancer, autophagy is highly context-specific depending on the cell type, tumour microenvironment, disease stage and external stimuli. Recently, the emerging role of autophagy as a double-edged sword in cancer has gained much attention. On one hand, autophagy suppresses malignant transformation by limiting the production of reactive oxygen species and DNA damage during tumour development. Subsequently, autophagy evolved to support the survival of cancer cells and promotes the tumourigenicity of cancer stem cells at established sites. Hence, autophagy is an attractive target for cancer therapeutics and researchers have been exploiting the use of autophagy modulators as adjuvant therapy. In this review, we present a summary of autophagy mechanism and controlling pathways, with emphasis on the dual-role of autophagy (double-edged sword) in cancer. This is followed by an overview of the autophagy modulation for cancer treatment and is concluded by a discussion on the current perspectives and future outlook of autophagy exploitation for precision medicine.

Keywords:  Autophagy; Cancer; LRG1; Precision Medicine; Treatment

DOI:  https://doi.org/10.1186/s13578-021-00570-z
Neurobiol Dis. 2021 Mar 19. pii: S0969-9961(21)00085-1. [Epub ahead of print] 105336

Inhibition of GSK-3 ameliorates the pathogenesis of Huntington's disease.

Ido Rippin, Katherina Bonder, Shirley Ben Joseph, Amar Sarsor, Lilach Vaks, Hagit Eldar-Finkelman.

  In Huntington's disease (HD), the mutant huntingtin (mHtt) accumulates as toxic aggregates in the striatum tissue, with deleterious effects on motor-coordination and cognitive functions. Reducing the levels of mHtt is therefore a promising therapeutic strategy. We have previously reported that GSK-3 is a negative regulator of the autophagy/lysosome pathway, which is responsible for intracellular degradation, and is critically important for maintaining neuronal vitality. Thus, we hypothesized that inhibition of GSK-3 may trigger mHtt clearance thereby reducing mHtt cytotoxicity and improving HD symptoms. Here, we demonstrate that depletion or suppression of autophagy results in a massive accumulation of mHtt aggregates. Accordingly, mHtt aggregates were localized in lysosomes, but, mostly mislocalized from lysosomes in the absence of functional autophagy. Overexpression of GSK-3, particularly the α isozyme, increased the number of mHtt aggregates, while silencing GSK-3α/β, or treatment with a selective GSK-3 inhibitor, L807mts, previously described by us, reduced the amounts of mHtt aggregates. This effect was mediated by increased autophagic and lysosomal activity. Treating R6/2 mouse model of HD with L807mts, reduced striatal mHtt aggregates and elevated autophagic and lysosomal markers. The L807mts treatment also reduced hyperglycemia and improved motor-coordination functions in these mice. In addition, L807mts restored the expression levels of Sirt1, a critical neuroprotective factor in the HD striatum, along with its targets BDNF, DRPP-32, and active Akt, all provide neurotrophic/pro-survival support and typically decline in the HD brain. Our results provide strong evidence for a role for GSK-3 in the regulation of mHtt dynamics, and demonstrate the benefits of GSK-3 inhibition in reducing mHtt toxicity, providing neuroprotective support, and improving HD symptoms.

Keywords:  Autophagy; GSK-3; GSK-3 inhibitor; Huntington's diseases; L807mts; Lysosome; Mutant huntingtin; R6/2 mice; Sirt1

DOI:  https://doi.org/10.1016/j.nbd.2021.105336
Clin Exp Pharmacol Physiol. 2021 Mar 22.

Targeting Autophagy in Neurodegenerative Diseases: from Molecular Mechanisms to Clinical Therapeutics.

Amir Ajoolabady, Hamid Aslkhodapasandhokmabad, Nils Henninger, Laurie J Demillard, Masoud Nikanfar, Alireza Nourazarian, Jun Ren.

  Many neurodegenerative diseases are associated with pathological aggregation of proteins in neurons. Autophagy is a natural self-cannibalization process that can act as a powerful mechanism to remove aged and damaged organelles as well as protein aggregates. It has been shown that promoting autophagy can attenuate or delay neurodegeneration by removing protein aggregates. In this paper, we will review the role of autophagy in Alzheimer's disease (AD), Parkinson's Disease (PD), and Huntington's Disease (HD) and discuss opportunities and challenges of targeting autophagy as a potential therapeutic avenue for treatment of these common neurodegenerative diseases.

Keywords:  Alzheimer’s disease (AD); Parkinson’s Disease (PD); and Huntington’s Disease (HD); autophagy; neurodegenerative disease

DOI:  https://doi.org/10.1111/1440-1681.13500
Nat Rev Cancer. 2021 Mar 23.

Autophagy in tumour immunity and therapy.

Houjun Xia, Douglas R Green, Weiping Zou.

Autophagy is a regulated mechanism that removes unnecessary or dysfunctional cellular components and recycles metabolic substrates. In response to stress signals in the tumour microenvironment, the autophagy pathway is altered in tumour cells and immune cells - thereby differentially affecting tumour progression, immunity and therapy. In this Review, we summarize our current understanding of the immunologically associated roles and modes of action of the autophagy pathway in cancer progression and therapy, and discuss potential approaches targeting autophagy to enhance antitumour immunity and improve the efficacy of current cancer therapy.

DOI: https://doi.org/10.1038/s41568-021-00344-2
J Transl Med. 2021 Mar 21. 19(1): 118

GRP78 in lung cancer.

Shengkai Xia, Wenzhe Duan, Wenwen Liu, Xinri Zhang, Qi Wang.

  Glucose-regulating protein 78 (GRP78) is a molecular chaperone in the endoplasmic reticulum (ER) that promotes folding and assembly of proteins, controls the quality of proteins, and regulates ER stress signaling through Ca2+ binding to the ER. In tumors, GRP78 is often upregulated, acting as a central stress sensor that senses and adapts to changes in the tumor microenvironment, mediating ER stress of cancer cells under various stimulations of the microenvironment to trigger the folding protein response. Increasing evidence has shown that GRP78 is closely associated with the progression and poor prognosis of lung cancer, and plays an important role in the treatment of lung cancer. Herein, we reviewed for the first time the functions and mechanisms of GRP78 in the pathological processes of lung cancer, including tumorigenesis, apoptosis, autophagy, progression, and drug resistance, giving a comprehensive understanding of the function of GRP78 in lung cancer. In addition, we also discussed the potential role of GRP78 as a prognostic biomarker and therapeutic target for lung cancer, which is conducive to improving the assessment of lung cancer and the development of new therapeutic interventions.

Keywords:  Autophagy; Endoplasmic reticulum; GRP78; Lung cancer; Unfolded protein response (UPR)

DOI:  https://doi.org/10.1186/s12967-021-02786-6
Biochem Biophys Res Commun. 2021 Mar 19. pii: S0006-291X(21)00364-8. [Epub ahead of print]552 191-195

Protein phosphatase 6 dissociates the Beclin 1/Vps34 complex and inhibits autophagy.

Nobuyuki Fujiwara, Shusaku Shibutani, Takashi Ohama, Koichi Sato.

  Autophagy is an evolutionarily conserved intracellular degradation system and is regulated by various signaling pathways including the Beclin 1/Vacuolar protein sorting 34 (Vps34) complex. Protein phosphatase 6 (PP6) is an essential serine/threonine phosphatase that regulates various biological processes. Recently, we found that PP6 protein is degraded by p62-dependent selective autophagy. In this study, we show that PP6 conversely inhibits autophagy. PP6 associate with the C-terminal region of Beclin 1, which is close to the binding region of Vps34. The protein levels of PP6 affect Beclin 1/Vps34 complex formation and phosphatase activity of PP6 is not involved in this. We also show that chemically induced PP6/Beclin 1 association leads to Vps34 dissociation from Beclin 1. Overall, our data reveal a novel regulatory mechanism for autophagy by PP6.

Keywords:  Autophagy; Beclin 1; Protein-protein interaction; Serine/threonine protein phosphatase 6

DOI:  https://doi.org/10.1016/j.bbrc.2021.02.136
Cell Death Dis. 2021 Mar 23. 12(4): 309

Autophagy-dependent survival is controlled with a unique regulatory network upon various cellular stress events.

Orsolya Kapuy, Marianna Holczer, Margita Márton, Tamás Korcsmáros.

Although autophagy is a type of programmed cell death, it is also essential for cell survival upon tolerable level of various stress events. For the cell to respond adequately to an external and/or internal stimulus induced by cellular stress, autophagy must be controlled in a highly regulated manner. By using systems biology techniques, here we explore the dynamical features of autophagy induction. We propose that the switch-like characteristic of autophagy induction is achieved by a control network, containing essential feedback loops of four components, so-called autophagy inducer, autophagy controller, mTORC1 and autophagy executor, respectively. We show how an autophagy inducer is capable to turn on autophagy in a cellular stress-specific way. The autophagy controller acts as a molecular switch and not only promotes autophagy but also blocks the permanent hyperactivation of the process via downregulating the autophagy inducer. In this theoretical analysis, we explore in detail the properties of all four proposed controlling elements and their connections. Here we also prove that the kinetic features of this control network can be considered accurate in various stress processes (such as starvation, endoplasmic reticulum stress and oxidative stress), even if the exact components may be different. The robust response of the resulting control network is essential during cellular stress.

DOI: https://doi.org/10.1038/s41419-021-03599-7
Curr Biol. 2021 Mar 18. pii: S0960-9822(21)00305-5. [Epub ahead of print]

Increased LRRK2 kinase activity alters neuronal autophagy by disrupting the axonal transport of autophagosomes.

C Alexander Boecker, Juliet Goldsmith, Dan Dou, Gregory G Cajka, Erika L F Holzbaur.

  Parkinson's disease-causing mutations in the leucine-rich repeat kinase 2 (LRRK2) gene hyperactivate LRRK2 kinase activity and cause increased phosphorylation of Rab GTPases, important regulators of intracellular trafficking. We found that the most common LRRK2 mutation, LRRK2-G2019S, dramatically reduces the processivity of autophagosome transport in neurons in a kinase-dependent manner. This effect was consistent across an overexpression model, neurons from a G2019S knockin mouse, and human induced pluripotent stem cell (iPSC)-derived neurons gene edited to express the G2019S mutation, and the effect was reversed by genetic or pharmacological inhibition of LRRK2. Furthermore, LRRK2 hyperactivation induced by overexpression of Rab29, a known activator of LRRK2 kinase, disrupted autophagosome transport to a similar extent. Mechanistically, we found that hyperactive LRRK2 recruits the motor adaptor JNK-interacting protein 4 (JIP4) to the autophagosomal membrane, inducing abnormal activation of kinesin that we propose leads to an unproductive tug of war between anterograde and retrograde motors. Disruption of autophagosome transport correlated with a significant defect in autophagosome acidification, suggesting that the observed transport deficit impairs effective degradation of autophagosomal cargo in neurons. Our results robustly link increased LRRK2 kinase activity to defects in autophagosome transport and maturation, further implicating defective autophagy in the pathogenesis of Parkinson's disease.

Keywords:  JIP4; LRRK2; Parkinson's disease; Rab29; autophagy; axonal transport

DOI:  https://doi.org/10.1016/j.cub.2021.02.061
Oxid Med Cell Longev. 2021 ;2021 6636510

The Regulation of ROS- and BECN1-Mediated Autophagy by Human Telomerase Reverse Transcriptase in Glioblastoma.

Xuelu Ding, Ziyang Nie, Zhaoyuan She, Xue Bai, Qiuhui Yang, Feng Wang, Fei Wang, Xin Geng.

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor with high morbidity and mortality. Human telomerase reverse transcriptase (hTERT), the catalytic subunit of human telomerase, is overexpressed in most cancers including GBM. It is well known that hTERT can compensate telomere shortening to immortalize cells. However, in addition to the canonical function, hTERT has the roles beyond canonical telomere maintenance. To further understand the effects of hTERT on glioblastoma progression, we investigated the role of hTERT in regulating autophagy-a conserved pathway, by which cells deliver cellular organic material and impaired organelles to the lysosomes for degradation and recycle these cargos to produce energy under a stressful condition. Our results showed that downregulation of hTERT impaired autophagy levels by suppressing BECN1/beclin-1 and induced an increase of reactive oxygen species (ROS), which resulted in cell death ultimately. On the contrary, overexpression of BECN1 or treating cells with the antioxidant N-acetylcysteine (NAC) could restore the survival of hTERT knockdown cells. Our study will provide an additional basis of telomerase-targeting therapy for future clinical anticancer treatment.

DOI: https://doi.org/10.1155/2021/6636510
Biochem Soc Trans. 2021 Mar 26. pii: BST20190236. [Epub ahead of print]

Parkinson's disease and mitophagy: an emerging role for LRRK2.

Francois Singh, Ian G Ganley.

  Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects around 2% of individuals over 60 years old. It is characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, which is thought to account for the major clinical symptoms such as tremor, slowness of movement and muscle stiffness. Its aetiology is poorly understood as the physiological and molecular mechanisms leading to this neuronal loss are currently unclear. However, mitochondrial and lysosomal dysfunction seem to play a central role in this disease. In recent years, defective mitochondrial elimination through autophagy, termed mitophagy, has emerged as a potential contributing factor to disease pathology. PINK1 and Parkin, two proteins mutated in familial PD, were found to eliminate mitochondria under distinct mitochondrial depolarisation-induced stress. However, PINK1 and Parkin are not essential for all types of mitophagy and such pathways occur in most cell types and tissues in vivo, even in the absence of overt mitochondrial stress - so-called basal mitophagy. The most common mutation in PD, that of glycine at position 2019 to serine in the protein kinase LRRK2, results in increased activity and this was recently shown to disrupt basal mitophagy in vivo. Thus, different modalities of mitophagy are affected by distinct proteins implicated in PD, suggesting impaired mitophagy may be a common denominator for the disease. In this short review, we discuss the current knowledge about the link between PD pathogenic mutations and mitophagy, with a particular focus on LRRK2.

Keywords:  Parkinsons disease; autophagy; leucine-rich repeat kinase; mitophagy

DOI:  https://doi.org/10.1042/BST20190236
J Agric Food Chem. 2021 Mar 23.

The Crosstalk between Autophagy and Apoptosis Is Necessary for Myogenic Differentiation.

Aiwen Jiang, Hongyun Guo, Wangjun Wu, Honglin Liu.

  Skeletal muscle is a major organ in animals, which constitutes over 40% of livestock body weight, and plays a critical role in metabolism and homeostasis in an organism. Autophagy and apoptosis are two major processes to determine cell fate. Recently, the importance of autophagy and apoptosis in myogenesis has been identified; however, their crosstalk is not well defined. In this study, we aimed to explore the relationship between apoptosis and autophagy during myogenic differentiation. The results showed that the level of autophagy was consistent with apoptosis during myogenic differentiation. The increased apoptosis activated autophagy, and then autophagy inhibited apoptosis in turn to prevent excessive apoptosis and maintain the stability of cells. The interaction between autophagy and apoptosis determines the balance of cell death and cell survival, allowing the skeletal muscle cells to differentiate normally.

Keywords:  apoptosis; autophagy; cell survival; myogenic differentiation

DOI:  https://doi.org/10.1021/acs.jafc.1c00140