bims-lymeca Biomed News
on Lysosome metabolism in cancer
Issue of 2022–12–18
seven papers selected by
Harilaos Filippakis, University of New England
  1. Lysosome signaling in cell survival and programmed cell death for cellular homeostasis.
  2. Editorial: Cell compartments and intracellular trafficking of lipids and proteins: Impact on biomedicine.
  3. Cell Type-Specific Metabolic Response to Amino Acid Starvation Dictates the Role of Sestrin2 in Regulation of mTORC1.
  4. Iron-induced cytotoxicity mediated by endolysosomal TRPML1 channels is reverted by TFEB.
  5. Endosomal lipid signaling reshapes the endoplasmic reticulum to control mitochondrial function.
  6. An open access, machine learning pipeline for high-throughput quantification of cell morphology.
  7. Autophagy inhibition and reactive oxygen species elimination by acetyl-CoA acetyltransferase 1 through fused in sarcoma protein to promote prostate cancer.
  1. J Cell Physiol. 2022 Dec 11.
    Lysosome signaling in cell survival and programmed cell death for cellular homeostasis.
    Srimanta Patra, Shankargouda Patil, Daniel J Klionsky, Sujit K Bhutia.
      Recent developments in lysosome biology have transformed our view of lysosomes from static garbage disposals that can also act as suicide bags to decidedly dynamic multirole adaptive operators of cellular homeostasis. Lysosome-governed signaling pathways, proteins, and transcription factors equilibrate the rate of catabolism and anabolism (autophagy to lysosomal biogenesis and metabolite pool maintenance) by sensing cellular metabolic status. Lysosomes also interact with other organelles by establishing contact sites through which they exchange cellular contents. Lysosomal function is critically assessed by lysosomal positioning and motility for cellular adaptation. In this setting, mechanistic target of rapamycin kinase (MTOR) is the chief architect of lysosomal signaling to control cellular homeostasis. Notably, lysosomes can orchestrate explicit cell death mechanisms, such as autophagic cell death and lysosomal membrane permeabilization-associated regulated necrotic cell death, to maintain cellular homeostasis. These lines of evidence emphasize that the lysosomes serve as a central signaling hub for cellular homeostasis.
    Keywords:  autophagy; lysosomal biogenesis; lysosomal membrane permeabilization; lysosome; mechanistic target of rapamycin kinase
    DOI:  https://doi.org/10.1002/jcp.30928
  2. Front Cell Dev Biol. 2022 ;10 1087214
    Editorial: Cell compartments and intracellular trafficking of lipids and proteins: Impact on biomedicine.
    Silvana Zanlungo, Carlos Enrich, Volker Gerke, Emily R Eden, María Isabel Colombo.
      
    Keywords:  Endosomes; cholesterol; disease models; lipid droplets; lysosomal storage diseases; lysosome-related organelles; lysosomes; membrane contact sites
    DOI:  https://doi.org/10.3389/fcell.2022.1087214
  3. Cells. 2022 Nov 30. pii: 3863. [Epub ahead of print]11(23):
    Cell Type-Specific Metabolic Response to Amino Acid Starvation Dictates the Role of Sestrin2 in Regulation of mTORC1.
    Biljana Blagojevic, Fadi Almouhanna, Gernot Poschet, Stefan Wölfl.
      Targeting cancer metabolism has become one of the strategies for a rational anti-tumor therapy. However, cellular plasticity, driven by a major regulator of cellular growth and metabolism, mTORC1, often leads toward treatment resistance. Sestrin2, a stress-inducible protein, has been described as an mTORC1 inhibitor upon various types of stress signals. Immune assays and online measurements of cellular bioenergetics were employed to investigate the nature of Sestrin2 regulation, and finally, by silencing the SESN2 gene, to identify the role of induced Sestrin2 upon a single amino acid deprivation in cancer cells of various origins. Our data suggest that a complex interplay of either oxidative, energetic, nutritional stress, or in combination, play a role in Sestrin2 regulation upon single amino acid deprivation. Therefore, cellular metabolic background and sequential metabolic response dictate Sestrin2 expression in the absence of an amino acid. While deprivations of essential amino acids uniformly induce Sestrin2 levels, non-essential amino acids regulate Sestrin2 differently, drawing a characteristic Sestrin2 expression fingerprint, which could serve as a first indication of the underlying cellular vulnerability. Finally, we show that canonical GCN2-ATF4-mediated Sestrin2 induction leads to mTORC1 inhibition only in amino acid auxotroph cells, where the amino acid cannot be replenished by metabolic reprogramming.
    Keywords:  Sestrin2; amino acid deprivation; mTORC1; metabolic adaptation; nutritional stress
    DOI:  https://doi.org/10.3390/cells11233863
  4. Cell Death Dis. 2022 Dec 16. 13(12): 1047
    Iron-induced cytotoxicity mediated by endolysosomal TRPML1 channels is reverted by TFEB.
    Belén Fernández, Pablo Olmedo, Fernando Gil, Elena Fdez, Yahaira Naaldijk, Pilar Rivero-Ríos, Franz Bracher, Christian Grimm, Grant C Churchill, Sabine Hilfiker.
      Increased brain iron content has been consistently reported in sporadic Parkinson's disease (PD) patients, and an increase in cytosolic free iron is known to cause oxidative stress and cell death. However, whether iron also accumulates in susceptible brain areas in humans or in mouse models of familial PD remains unknown. In addition, whilst the lysosome functions as a critical intracellular iron storage organelle, little is known about the mechanisms underlying lysosomal iron release and how this process is influenced by lysosome biogenesis and/or lysosomal exocytosis. Here, we report an increase in brain iron content also in PD patients due to the common G2019S-LRRK2 mutation as compared to healthy age-matched controls, whilst differences in iron content are not observed in G2019S-LRRK2 knockin as compared to control mice. Chemically triggering iron overload in cultured cells causes cytotoxicity via the endolysosomal release of iron which is mediated by TRPML1. TFEB expression reverts the iron overload-associated cytotoxicity by causing lysosomal exocytosis, which is dependent on a TRPML1-mediated increase in cytosolic calcium levels. Therefore, approaches aimed at increasing TFEB levels, or pharmacological TRPML1 activation in conjunction with iron chelation may prove beneficial against cell death associated with iron overload conditions such as those associated with PD.
    DOI:  https://doi.org/10.1038/s41419-022-05504-2
  5. Science. 2022 Dec 16. 378(6625): eabq5209
    Endosomal lipid signaling reshapes the endoplasmic reticulum to control mitochondrial function.
    Wonyul Jang, Dmytro Puchkov, Paula Samsó, YongTian Liang, Michal Nadler-Holly, Stephan J Sigrist, Ulrich Kintscher, Fan Liu, Kamel Mamchaoui, Vincent Mouly, Volker Haucke.
      Cells respond to fluctuating nutrient supply by adaptive changes in organelle dynamics and in metabolism. How such changes are orchestrated on a cell-wide scale is unknown. We show that endosomal signaling lipid turnover by MTM1, a phosphatidylinositol 3-phosphate [PI(3)P] 3-phosphatase mutated in X-linked centronuclear myopathy in humans, controls mitochondrial morphology and function by reshaping the endoplasmic reticulum (ER). Starvation-induced endosomal recruitment of MTM1 impairs PI(3)P-dependent contact formation between tubular ER membranes and early endosomes, resulting in the conversion of ER tubules into sheets, the inhibition of mitochondrial fission, and sustained oxidative metabolism. Our results unravel an important role for early endosomal lipid signaling in controlling ER shape and, thereby, mitochondrial form and function to enable cells to adapt to fluctuating nutrient environments.
    DOI:  https://doi.org/10.1126/science.abq5209
  6. STAR Protoc. 2022 Dec 15. pii: S2666-1667(22)00827-9. [Epub ahead of print]4(1): 101947
    An open access, machine learning pipeline for high-throughput quantification of cell morphology.
    Emma M Welter, Oksana Kosyk, Anthony S Zannas.
      Cell morphology is influenced by many factors and can be used as a phenotypic marker. Here we describe a machine-learning-based protocol for high-throughput morphological measurement of human fibroblasts using a standard fluorescence microscope and the pre-existing, open access software ilastik for cell body identification, ImageJ/Fiji for image overlay, and CellProfiler for morphological quantification. Because this protocol overlays nuclei with their cell bodies and relies on coloration differences, it can be broadly applied to other cell types beyond fibroblasts. For details on the use and execution of this protocol, please also refer to Leung et al. (2022).1.
    Keywords:  Cell Biology; Cell culture; Computer sciences; Microscopy
    DOI:  https://doi.org/10.1016/j.xpro.2022.101947
  7. BMC Cancer. 2022 Dec 14. 22(1): 1313
    Autophagy inhibition and reactive oxygen species elimination by acetyl-CoA acetyltransferase 1 through fused in sarcoma protein to promote prostate cancer.
    Jingqian Guan, Xizi Jiang, Yaoxing Guo, Wenhui Zhao, Ji Li, Yizhuo Li, Ming Cheng, Lin Fu, Yue Zhao, Qingchang Li.
       BACKGROUND: Prostate cancer is a major health issue affecting the male population worldwide, and its etiology remains relatively unknown. As presented on the Gene Expression Profiling Interactive Analysis database, acetyl-CoA acetyltransferase 1 (ACAT1) acts as a prostate cancer-promoting factor. ACAT1 expression in prostate cancer tissues is considerably higher than that in normal tissues, leading to a poor prognosis in patients with prostate cancer. Here, we aimed to study the role of the ACAT1-fused in sarcoma (FUS) complex in prostate cancer and identify new targets for the diagnosis and treatment of the disease.
    METHODS: We conducted immunohistochemical analysis of 57 clinical samples and in vitro and in vivo experiments using a mouse model and plasmid constructs to determine the expression of ACAT1 in prostate cancer.
    RESULTS: The relationship between the expression of ACAT1 and the Gleason score was significant. The expression of ACAT1 was higher in tissues with a Gleason score of > 7 than in tissues with a Gleason score of ≤7 (P = 0.0011). In addition, we revealed that ACAT1 can interact with the FUS protein.
    CONCLUSIONS: In prostate cancer, ACAT1 promotes the expression of P62 and Nrf2 through FUS and affects reactive oxygen species scavenging. These effects are due to the inhibition of autophagy by ACAT1. That is, ACAT1 promotes prostate cancer by inhibiting autophagy and eliminating active oxygen species. The expression of ACAT1 is related to prostate cancer. Studying the underlying mechanism may provide a new perspective on the treatment of prostate cancer.
    Keywords:  ACAT1; Autophagy; FUS; Prostate cancer; Reactive oxygen species
    DOI:  https://doi.org/10.1186/s12885-022-10426-5
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