bims-apauto 2022-07-24 papers

bims-apauto

Biomed News

on Apoptosis and autophagy

Issue of 2022–07–24
eight papers selected by
Su Hyun Lee, Seoul National University

The Role of Membrane-Associated E3 Ubiquitin Ligases in Cancer.
Autophagy in health and disease: From molecular mechanisms to therapeutic target.
Possible role of autophagy induced by COVID-19 in cancer progression, chemo-resistance, and tumor recurrence.
Mechanisms of cancer cell death induction by paclitaxel: an updated review.
Development of Strigolactones as Novel Autophagy/Mitophagy Inhibitors against Colorectal Cancer Cells by Blocking the Autophagosome-Lysosome Fusion.
Autophagy promotes GSDME-mediated pyroptosis via intrinsic and extrinsic apoptotic pathways in cobalt chloride-induced hypoxia reoxygenation-acute kidney injury.
Regulation of Metabolism by Mitochondrial MUL1 E3 Ubiquitin Ligase.
Mitochondrial RNA methyltransferase TRMT61B is a new, potential biomarker and therapeutic target for highly aneuploid cancers.

Front Pharmacol. 2022 ;13 928794

The Role of Membrane-Associated E3 Ubiquitin Ligases in Cancer.

Xuankun Chen, Li Jiang, Zhesheng Zhou, Bo Yang, Qiaojun He, Chengliang Zhu, Ji Cao.

  The cell membrane system comprises the plasma membrane, endoplasmic reticulum, Golgi apparatus, lysosome, mitochondria, and nuclear membrane, which are essential for maintaining normal physiological functions of cells. The proteins associated with these membrane-organelles are frequently modified to regulate their functions, the most common of which is ubiquitin modification. So far, many ubiquitin E3 ligases anchored in the membrane system have been identified as critical players facilitating intracellular biofunctions whose dysfunction is highly related to cancer. In this review, we summarized membrane-associated E3 ligases and revealed their relationship with cancer, which is of great significance for discovering novel drug targets of cancer and may open up new avenues for inducing ubiquitination-mediated degradation of cancer-associated membrane proteins via small chemicals such as PROTAC and molecular glue.

Keywords:  E3 ligases; PROTAC (proteolysis-targeting chimeric molecule); cancer; cell membrane system; drug targets

DOI:  https://doi.org/10.3389/fphar.2022.928794
MedComm (2020). 2022 Sep;3(3): e150

Autophagy in health and disease: From molecular mechanisms to therapeutic target.

Guang Lu, Yu Wang, Yin Shi, Zhe Zhang, Canhua Huang, Weifeng He, Chuang Wang, Han-Ming Shen.

  Macroautophagy/autophagy is an evolutionally conserved catabolic process in which cytosolic contents, such as aggregated proteins, dysfunctional organelle, or invading pathogens, are sequestered by the double-membrane structure termed autophagosome and delivered to lysosome for degradation. Over the past two decades, autophagy has been extensively studied, from the molecular mechanisms, biological functions, implications in various human diseases, to development of autophagy-related therapeutics. This review will focus on the latest development of autophagy research, covering molecular mechanisms in control of autophagosome biogenesis and autophagosome-lysosome fusion, and the upstream regulatory pathways including the AMPK and MTORC1 pathways. We will also provide a systematic discussion on the implication of autophagy in various human diseases, including cancer, neurodegenerative disorders (Alzheimer disease, Parkinson disease, Huntington's disease, and Amyotrophic lateral sclerosis), metabolic diseases (obesity and diabetes), viral infection especially SARS-Cov-2 and COVID-19, cardiovascular diseases (cardiac ischemia/reperfusion and cardiomyopathy), and aging. Finally, we will also summarize the development of pharmacological agents that have therapeutic potential for clinical applications via targeting the autophagy pathway. It is believed that decades of hard work on autophagy research is eventually to bring real and tangible benefits for improvement of human health and control of human diseases.

Keywords:  SARS‐CoV‐2; autophagy; cancer; cardiovascular diseases; metabolic diseases; neurodegenerative diseases

DOI:  https://doi.org/10.1002/mco2.150
Infect Agent Cancer. 2022 Jul 18. 17(1): 38

Possible role of autophagy induced by COVID-19 in cancer progression, chemo-resistance, and tumor recurrence.

Hamidreza Zalpoor, Abdullatif Akbari, Negar Nayerain Jazi, Mahsa Liaghat, Maryam Bakhtiyari.

  COVID-19 infection is a serious threat to patients with primary diseases, especially multiple cancers. Studies suggest that cancer patients are one of the most susceptible populations to experience severe COVID-19 and death. In addition, a number of studies suggest various mechanisms for SARS-CoV-2 in cancer progression. In this study, we discussed the role of SARS-CoV-2 in the induction of autophagy and we hypothesized that autophagy induced by COVID-19 not only can contribute to viral replication but also potentially can lead to cancer progression, chemo-resistance, and tumor recurrence in multiple cancer patients. Therefore, targeting autophagy-related signaling pathways and cellular and molecular processes could be a potentially promising therapeutic approach for cancer patients with COVID-19. Hence, this study can shed light on a new window on the management of such patients. However, more investigations in the future are required to understand other pathological effects of COVID-19 infection on cancer patients to provide new therapeutic strategies to combat these complications in these patients.

Keywords:  Autophagy; COVID-19; Cancer progression; Chemo-resistance; SARS-CoV-2; Tumor recurrence

DOI:  https://doi.org/10.1186/s13027-022-00450-2
Apoptosis. 2022 Jul 18.

Mechanisms of cancer cell death induction by paclitaxel: an updated review.

Shuang Zhao, Yufei Tang, Ruohan Wang, Masoud Najafi.

  Chemoresistance of cancer cells is a major problem in treating cancer. Knowledge of how cancer cells may die or resist cancer drugs is critical to providing certain strategies to overcome tumour resistance to treatment. Paclitaxel is known as a chemotherapy drug that can suppress the proliferation of cancer cells by inducing cell cycle arrest and induction of mitotic catastrophe. However, today, it is well known that paclitaxel can induce multiple kinds of cell death in cancers. Besides the induction of mitotic catastrophe that occurs during mitosis, paclitaxel has been shown to induce the expression of several pro-apoptosis mediators. It also can modulate the activity of anti-apoptosis mediators. However, certain cell-killing mechanisms such as senescence and autophagy can increase resistance to paclitaxel. This review focuses on the mechanisms of cell death, including apoptosis, mitotic catastrophe, senescence, autophagic cell death, pyroptosis, etc., following paclitaxel treatment. In addition, mechanisms of resistance to cell death due to exposure to paclitaxel and the use of combinations to overcome drug resistance will be discussed.

Keywords:  Apoptosis; Autophagic cell death; Cancer; Mitotic catastrophe; Paclitaxel; Senescence

DOI:  https://doi.org/10.1007/s10495-022-01750-z
J Med Chem. 2022 Jul 19.

Development of Strigolactones as Novel Autophagy/Mitophagy Inhibitors against Colorectal Cancer Cells by Blocking the Autophagosome-Lysosome Fusion.

Shu-Ting Yang, Jin-Bao Fan, Ting-Ting Liu, Shuai Ning, Jia-Hao Xu, Ying-Jun Zhou, Xu Deng.

Inhibition of autophagy has been widely viewed as a promising strategy for anticancer therapy. However, few effective and specific autophagy inhibitors have been reported. Herein, we described the design, synthesis, and biological characteristics of new analogues of strigolactones (SLs), an emerging class of plant hormones, against colorectal cancers. Among them, an enantiopure analogue 6 exerted potent and selective cytotoxicity against colorectal cancer cells, but not normal human colon mucosal epithelial cells, which were further confirmed by the plate colony formation assay. Moreover, it significantly inhibited tumor growth in an HCT116 xenograft mouse model with low toxicity. Mechanistically, it is associated with selective induction of cell apoptosis and cell cycle arrest. Remarkably, 6 acted as a potent autophagy/mitophagy inhibitor by selectively increasing the autophagic flux while blocking the autophagosome-lysosome fusion in HCT116 cells. This study features stereo-defined SLs as novel autophagy inhibitors with high cancer cell specificity, which paves a new path for anticolorectal cancer therapy.

DOI: https://doi.org/10.1021/acs.jmedchem.2c00275
Ecotoxicol Environ Saf. 2022 Jul 18. pii: S0147-6513(22)00721-7. [Epub ahead of print]242 113881

Autophagy promotes GSDME-mediated pyroptosis via intrinsic and extrinsic apoptotic pathways in cobalt chloride-induced hypoxia reoxygenation-acute kidney injury.

Wenna Liu, Yujin Gan, Yun Ding, Lina Zhang, Xiaojing Jiao, Lu Liu, Huixia Cao, Yue Gu, Lei Yan, Yanliang Wang, Limeng Wang, Song Chen, Fengmin Shao.

  Cobalt is a transition element that abundantly exists in the environment. Besides direct hypoxia stress, cobalt ions indirectly induce hypoxia-reoxygenation injury (HRI), the main cause of acute kidney injury (AKI), a life-threatening clinical syndrome characterized by the necrosis of the proximal tubular epithelial cells (PTECs) and inflammation. Pyroptosis, a type of inflammatory programmed cell death, might play an essential role in HRI-AKI. However, whether pyroptosis is involved in cobalt chloride (CoCl2)-induced HRI-AKI remains unknown. Autophagy is a cellular biological process maintaining cell homeostasis that is involved in cell damage in AKI, yet the underlying regulatory mechanism of autophagy on pyroptosis has not been fully understood. In this study, the in vitro and in vivo models of CoCl2-induced HRI-AKI were established with HK-2 cell line and C57BL/6J mouse. Pyroptosis-related markers were detected with western blotting and immunofluorescence assays, and results showed that gasdermin E (GSDME)-mediated pyroptosis was involved in the cell damage in HRI-AKI. Specific chemical inhibitors of caspase 3, caspase 8, and caspase 9 significantly inhibited GSDME-mediated pyroptosis, verifying that GSDME-mediated pyroptosis was induced via the activation of caspase 3/8/9. The western blotting and immunofluorescence assays were adopted to detect the accumulation of the autophagosomes, and results suggested that HRI increased the autophagic level. The effects of autophagy on apoptosis and pyroptosis were evaluated using lentivirus transfection assays to knock down autophagy-specific genes atg5 and fip200, and results demonstrated that autophagy induced GSDME-mediated pyroptosis via apoptotic pathways in HRI-AKI. Our results revealed the involvement of GSDME-mediated pyroptosis in CoCl2-induced HRI-AKI and promoted the understanding of the regulatory mechanism of GSDME cleavage. Our study might provide a potential therapeutic target for HRI-AKI, and will be helpful for the risk evaluation of cobalt exposure.

Keywords:  Acute kidney injury; Apoptosis; Autophagy; Cobalt chloride; Gasdermin E; Pyroptosis

DOI:  https://doi.org/10.1016/j.ecoenv.2022.113881
Front Cell Dev Biol. 2022 ;10 904728

Regulation of Metabolism by Mitochondrial MUL1 E3 Ubiquitin Ligase.

Lucia Cilenti, Rohit Mahar, Jacopo Di Gregorio, Camilla T Ambivero, Matthew E Merritt, Antonis S Zervos.

  MUL1 is a multifunctional E3 ubiquitin ligase that is involved in various pathophysiological processes including apoptosis, mitophagy, mitochondrial dynamics, and innate immune response. We uncovered a new function for MUL1 in the regulation of mitochondrial metabolism. We characterized the metabolic phenotype of MUL1(-/-) cells using metabolomic, lipidomic, gene expression profiling, metabolic flux, and mitochondrial respiration analyses. In addition, the mechanism by which MUL1 regulates metabolism was investigated, and the transcription factor HIF-1α, as well as the serine/threonine kinase Akt2, were identified as the mediators of the MUL1 function. MUL1 ligase, through K48-specific polyubiquitination, regulates both Akt2 and HIF-1α protein level, and the absence of MUL1 leads to the accumulation and activation of both substrates. We used specific chemical inhibitors and activators of HIF-1α and Akt2 proteins, as well as Akt2(-/-) cells, to investigate the individual contribution of HIF-1α and Akt2 proteins to the MUL1-specific phenotype. This study describes a new function of MUL1 in the regulation of mitochondrial metabolism and reveals how its downregulation/inactivation can affect mitochondrial respiration and cause a shift to a new metabolic and lipidomic state.

Keywords:  Akt2; HIF-1α; MUL1; metabolic flux; mitochondrial metabolism

DOI:  https://doi.org/10.3389/fcell.2022.904728
Cell Death Differ. 2022 Jul 22.

Mitochondrial RNA methyltransferase TRMT61B is a new, potential biomarker and therapeutic target for highly aneuploid cancers.

Alberto Martín, Carolina Epifano, Borja Vilaplana-Marti, Iván Hernández, Rocío I R Macías, Ángel Martínez-Ramírez, Ana Cerezo, Pablo Cabezas-Sainz, Maria Garranzo-Asensio, Sandra Amarilla-Quintana, Déborah Gómez-Domínguez, Eduardo Caleiras, Jordi Camps, Gonzalo Gómez-López, Marta Gómez de Cedrón, Ana Ramírez de Molina, Rodrigo Barderas, Laura Sánchez, Susana Velasco-Miguel, Ignacio Pérez de Castro.

Despite being frequently observed in cancer cells, chromosomal instability (CIN) and its immediate consequence, aneuploidy, trigger adverse effects on cellular homeostasis that need to be overcome by anti-stress mechanisms. As such, these safeguard responses represent a tumor-specific Achilles heel, since CIN and aneuploidy are rarely observed in normal cells. Recent data have revealed that epitranscriptomic marks catalyzed by RNA-modifying enzymes change under various stress insults. However, whether aneuploidy is associated with such RNA modifying pathways remains to be determined. Through an in silico search for aneuploidy biomarkers in cancer cells, we found TRMT61B, a mitochondrial RNA methyltransferase enzyme, to be associated with high levels of aneuploidy. Accordingly, TRMT61B protein levels are increased in tumor cell lines with an imbalanced karyotype as well as in different tumor types when compared to control tissues. Interestingly, while TRMT61B depletion induces senescence in melanoma cell lines with low levels of aneuploidy, it leads to apoptosis in cells with high levels. The therapeutic potential of these results was further validated by targeting TRMT61B in transwell and xenografts assays. We show that TRM61B depletion reduces the expression of several mitochondrial encoded proteins and limits mitochondrial function. Taken together, these results identify a new biomarker of aneuploidy in cancer cells that could potentially be used to selectively target highly aneuploid tumors.

DOI: https://doi.org/10.1038/s41418-022-01044-6