bims-lymeca 2022-01-30 papers

bims-lymeca

Biomed News

on Lysosome metabolism in cancer

Issue of 2022–01–30
ten papers selected by
Harilaos Filippakis, Harvard University

Endosomal cargo recycling mediated by Gpa1 and Phosphatidylinositol-3-Kinase is inhibited by glucose starvation.
Degradation of nuclear components via different autophagy pathways.
Increase in the sensitivity to PLX4720 through inhibition of transcription factor EB-dependent autophagy in BRAF inhibitor-resistant cells.
USP17 is required for peripheral trafficking of lysosomes.
Lysosomal peptidases - Intriguing roles in cancer progression and neurodegeneration.
The mixed blessing of AMPK signaling in Cancer treatments.
Relevance of lysosomal Ca2+ signalling machinery in cancer.
Lysosome-targeted ruthenium(II) complexes induce both apoptosis and autophagy in HeLa cells.
Crucial Players for Inter-Organelle Communication: PI5P4Ks and Their Lipid Product PI-4,5-P2 Come to the Surface.
The impact of DAPK1 and mTORC1 signaling association on autophagy in cancer.

Mol Biol Cell. 2022 Jan 26. mbcE21040163

Endosomal cargo recycling mediated by Gpa1 and Phosphatidylinositol-3-Kinase is inhibited by glucose starvation.

Kamilla Me Laidlaw, Katherine M Paine, Daniel D Bisinski, Grant Calder, Karen Hogg, Sophia Ahmed, Sally James, Peter J O'Toole, Chris MacDonald.

Cell surface protein trafficking is regulated in response to nutrient availability, with multiple pathways directing surface membrane proteins to the lysosome for degradation in response to suboptimal extracellular nutrients. Internalised protein and lipid cargoes recycle back to the surface efficiently in glucose replete conditions, but this trafficking is attenuated following glucose starvation. We find cells with either reduced or hyperactive phosphatidylinositol 3-kinase (PI3K) activity are defective for recycling. Furthermore, we find the yeast Gα subunit Gpa1, an endosomal PI3K effector, is required for surface recycling of cargoes. Following glucose starvation, mRNA and protein levels of a distinct Gα subunit Gpa2 are elevated following nuclear translocation of Mig1, which inhibits recycling of various cargoes. As Gpa1 and Gpa2 interact at the surface where Gpa2 concentrates during glucose starvation, we propose this disrupts PI3K activity required for recycling, potentially diverting Gpa1 to the surface and interfering with its endosomal role in recycling. In support of this model, glucose starvation and over-expression of Gpa2 alters PI3K endosomal phosphoinositide production. Glucose deprivation therefore triggers a survival mechanism to increase retention of surface cargoes in endosomes and promote their lysosomal degradation.

DOI: https://doi.org/10.1091/mbc.E21-04-0163
Trends Cell Biol. 2022 Jan 20. pii: S0962-8924(21)00267-1. [Epub ahead of print]

Degradation of nuclear components via different autophagy pathways.

Ziyang Li, Hitoshi Nakatogawa.

  Eukaryotic cells have evolved different modes of autophagy, including macroautophagy and microautophagy, to deliver their own components to lysosomes or vacuoles for degradation. While an increasing body of research has established that autophagy plays pivotal roles for the maintenance and regulation of various cellular constituents, recent studies have begun to reveal that parts of the nucleus, for example, nucleus-derived vesicles and nuclear proteins, also become targets of autophagic degradation in different physiological or pathological contexts, including nutrient deprivation, defective nuclear pore complex (NPC) assembly, DNA damage, cellular senescence, and oncogenic insults. Here, we overview our current knowledge on the mechanisms and physiological roles of these 'nucleophagy' pathways and discuss their possible interplays and remaining issues.

Keywords:  autophagy; intracellular degradation; lysosomes; nuclear pore complexes; nucleus; vacuoles

DOI:  https://doi.org/10.1016/j.tcb.2021.12.008
Toxicol Res. 2022 Jan;38(1): 35-44

Increase in the sensitivity to PLX4720 through inhibition of transcription factor EB-dependent autophagy in BRAF inhibitor-resistant cells.

Hojin Yeom, Sung-Hee Hwang, Hye-Gyo Kim, Michael Lee.

  Long-term treatment with oncogenic BRAF inhibitors confers resistance to BRAF inhibitor monotherapy. In this study, a combination treatment strategy with autophagy inhibitors was proposed to increase the sensitivity of BRAF mutant containing A375P melanoma cells that have developed resistance to BRAF inhibitors. We found that the A375P/Multi-drug resistance (A375P/Mdr) cells, which are resistant to both BRAF inhibitors and MEK inhibitors, exhibited a higher basal autophagic flux compared to their parental A375P cells, as determined by tandem mRFP-GFP-tagged LC3 imaging assay and LC3 conversion. In addition, transcription factor EB (TFEB), which acts as a transcription factor regulating the transcription of autophagy-related genes, was much more localized in the nucleus in A375P/Mdr cells than in A375P cells, indicating that the increase in basal autophagic flux was TFEB-dependent. In particular, the overexpression of an activated form of TFEB (TFEBAA) caused a modest increase in PLX4720 resistance in A375P/Mdr cells. Interestingly, treatment with early stage autophagy inhibitors reversed BRAF inhibitor-induced resistance, whereas late autophagy inhibition did not. In contrast, inhibition of ER stress by 4-phenylbutyric acid suppressed basal autophagic flux. Moreover, ER stress inhibition significantly remarkably inhibited the nuclear localization of TFEB, resulting in an increase in the sensitivity of A375P/Mdr cells to PLX4720. Taken together, these results suggest that autophagy may be an important mechanism of acquired resistance to BRAF inhibitors. Thus, targeting autophagy may be suitable for the treatment of tumors resistant to BRAF inhibitor.

Keywords:  Autophagy; BRAF inhibitor; Cancer; Drug resistance; PLX4720; TFEB

DOI:  https://doi.org/10.1007/s43188-021-00109-x
EMBO Rep. 2022 Jan 26. e51932

USP17 is required for peripheral trafficking of lysosomes.

Jia Lin, Aidan P McCann, Naphannop Sereesongsaeng, Jonathan M Burden, Alhareth A Alsa'd, Roberta E Burden, Ileana Micu, Richard Williams, Sandra Van Schaeybroeck, Emma Evergren, Paul Mullan, Jeremy C Simpson, Christopher J Scott, James F Burrows.

  Expression of the deubiquitinase USP17 is induced by multiple stimuli, including cytokines (IL-4/6), chemokines (IL-8, SDF1), and growth factors (EGF), and several studies indicate it is required for cell proliferation and migration. However, the mechanisms via which USP17 impacts upon these cellular functions are unclear. Here, we demonstrate that USP17 depletion prevents peripheral lysosome positioning, as well as trafficking of lysosomes to the cell periphery in response to EGF stimulation. Overexpression of USP17 also increases secretion of the lysosomal protease cathepsin D. In addition, USP17 depletion impairs plasma membrane repair in cells treated with the pore-forming toxin streptolysin O, further indicating that USP17 is required for lysosome trafficking to the plasma membrane. Finally, we demonstrate that USP17 can deubiquitinate p62, and we propose that USP17 can facilitate peripheral lysosome trafficking by opposing the E3 ligase RNF26 to untether lysosomes from the ER and facilitate lysosome peripheral trafficking, lysosome protease secretion, and plasma membrane repair.

Keywords:  EGF; USP17; exocytosis; lysosome

DOI:  https://doi.org/10.15252/embr.202051932
FEBS Open Bio. 2022 Jan 23.

Lysosomal peptidases - Intriguing roles in cancer progression and neurodegeneration.

Janko Kos, Ana Mitrović, Milica Perišić Nanut, Anja Pišlar.

  Lysosomal peptidases are hydrolytic enzymes capable of digesting waste proteins that are targeted to lysosomes via endocytosis and autophagy. Besides intracellular protein catabolism, they play more specific roles in several other cellular processes and pathologies, either within lysosomes, upon secretion into the cell cytoplasm or extracellular space, or bound to the plasma membrane. In cancer, lysosomal peptidases are generally associated with disease progression, as they participate in crucial processes leading to changes in cell morphology, signaling, migration, and invasion, and finally metastasis. However, they can also enhance the mechanisms resulting in cancer regression, such as apoptosis of tumor cells or antitumor immune responses. Lysosomal peptidases have also been identified as hallmarks of aging and neurodegeneration, playing roles in oxidative stress, mitochondrial dysfunction, abnormal intercellular communication, dysregulated trafficking, and the deposition of protein aggregates in neuronal cells. Furthermore, deficiencies in lysosomal peptidases may result in other pathological states, such as lysosomal storage disease. The aim of this review is to highlight the role of lysosomal peptidases in particular pathological processes of cancer and neurodegeneration and to address the potential of lysosomal peptidases in diagnosing and treating patients.

Keywords:  Cancer; Cathepsins; Lysosomes; Neurodegeneration; Peptidases

DOI:  https://doi.org/10.1002/2211-5463.13372
BMC Cancer. 2022 Jan 25. 22(1): 105

The mixed blessing of AMPK signaling in Cancer treatments.

Mehrshad Sadria, Deokhwa Seo, Anita T Layton.

   BACKGROUND: Nutrient acquisition and metabolism pathways are altered in cancer cells to meet bioenergetic and biosynthetic demands. A major regulator of cellular metabolism and energy homeostasis, in normal and cancer cells, is AMP-activated protein kinase (AMPK). AMPK influences cell growth via its modulation of the mechanistic target of Rapamycin (mTOR) pathway, specifically, by inhibiting mTOR complex mTORC1, which facilitates cell proliferation, and by activating mTORC2 and cell survival. Given its conflicting roles, the effects of AMPK activation in cancer can be counter intuitive. Prior to the establishment of cancer, AMPK acts as a tumor suppressor. However, following the onset of cancer, AMPK has been shown to either suppress or promote cancer, depending on cell type or state.
METHODS: To unravel the controversial roles of AMPK in cancer, we developed a computational model to simulate the effects of pharmacological maneuvers that target key metabolic signalling nodes, with a specific focus on AMPK, mTORC, and their modulators. Specifically, we constructed an ordinary differential equation-based mechanistic model of AMPK-mTORC signaling, and parametrized the model based on existing experimental data.
RESULTS: Model simulations were conducted to yield the following predictions: (i) increasing AMPK activity has opposite effects on mTORC depending on the nutrient availability; (ii) indirect inhibition of AMPK activity through inhibition of sirtuin 1 (SIRT1) only has an effect on mTORC activity under conditions of low nutrient availability; (iii) the balance between cell proliferation and survival exhibits an intricate dependence on DEP domain-containing mTOR-interacting protein (DEPTOR) abundance and AMPK activity; (iv) simultaneous direct inhibition of mTORC2 and activation of AMPK is a potential strategy for suppressing both cell survival and proliferation.
CONCLUSIONS: Taken together, model simulations clarify the competing effects and the roles of key metabolic signalling pathways in tumorigenesis, which may yield insights on innovative therapeutic strategies.

Keywords:  AMPK; Cancer; Dynamical system; Metabolism; mTORC

DOI:  https://doi.org/10.1186/s12885-022-09211-1
Cell Calcium. 2022 Jan 10. pii: S0143-4160(22)00014-8. [Epub ahead of print]102 102539

Relevance of lysosomal Ca2+ signalling machinery in cancer.

Samantha Barbonari, Antonella D'Amore, Fioretta Palombi, Paola De Cesaris, John Parrington, Anna Riccioli, Antonio Filippini.

In comparison with normal cells, cancer cells are equipped with a higher number of lysosomes, involved in degradative and non-degradative roles. In particular, the lysosome is a Ca2+signalling hub, and the enhancement of this interconnected machinery in cancer cells has recently prompted investigations into the role that lysosomal ion channels play in oncology. The present review reports findings about the emerging role of lysosomal Ca2+channels: Two-Pore Channels (TPCs), Transient Receptor Potential Cation Channels (TRPMLs; mucolipins), and Purinergic X Receptor 4 (P2×4R), in a variety of cancer models, highlighting their impact on crucial functions such as the regulation of autophagy and the composition of the tumour microenvironment, including the secretion-mediated interplay with immune and endothelial cells. Notably, recent evidence indicates that, by regulating tumour secretome, lysosomal Ca2+ signalling can affect the composition of the tumour-infiltrating immune cell repertoire. Intriguingly, the data so far available show that the protumoral/antitumoral role of lysosomal Ca2+ channels can differ according to the specific genetic context, types of cancer and the malignancy stage, and signals from the microenvironment.

DOI: https://doi.org/10.1016/j.ceca.2022.102539
J Inorg Biochem. 2022 Jan 19. pii: S0162-0134(22)00018-6. [Epub ahead of print]229 111729

Lysosome-targeted ruthenium(II) complexes induce both apoptosis and autophagy in HeLa cells.

Nan-Lian Pan, Jia-Xin Liao, Min-Ying Huang, Yu-Qing Zhang, Jia-Xi Chen, Ze-Wei Zhang, Zhi-Xin Yang, Xiong-En Long, Xing-Tao Wu, Jing Sun.

  Ruthenium complexes with good biological properties have attracted increasing attention in recent decades. In this work, three ruthenium polypyridine complexes containing 5-fluorouracil derivatives as ligands, [Ru(bpy)2(L)]2+ (Ru1), [Ru(phen)2(L)]2+ (Ru2), [Ru(dip)2(L)]2+ (Ru3) (L = 1-((1,10-phenanthroline-5-amino) pentyl)-5-fluorouracil; bpy = 2,2'-bipyridine; phen =1,10-phenanthroline; dip = 4,7-diphenyl-1,10-phenanthroline), were synthesized and characterized. Based on in vitro cytotoxicity tests, Ru3 (IC50 = 7.35 ± 0.39 μM) showed the best anticancer activity among three compounds in the selected cell lines. It is worth noting that Ru3 also exerts less cytotoxicity on LO2 cell lines, with an IC50 value 5 times higher than that on HeLa cells, indicating its selective activity. Mechanism studies revealed that Ru3 can specifically target lysosomes and induce cell apoptosis in a caspase-dependent manner. Specifically, Ru3 can arrest cell cycle at the G0/G1 phase, increase the intracellular reactive oxygen species (ROS) level, and then damage DNA. In short, Ru3 can eventually cause cell death through the synergy of inducing apoptosis and autophagy, which was further proven by western blot assay results.

Keywords:  Anticancer; Apoptosis; Autophagy; Cytotoxicity; Lysosomes; Ru(II) complexes

DOI:  https://doi.org/10.1016/j.jinorgbio.2022.111729
Front Cell Dev Biol. 2021 ;9 791758

Crucial Players for Inter-Organelle Communication: PI5P4Ks and Their Lipid Product PI-4,5-P2 Come to the Surface.

Archna Ravi, Lavinia Palamiuc, Brooke M Emerling.

  While organelles are individual compartments with specialized functions, it is becoming clear that organellar communication is essential for maintaining cellular homeostasis. This cooperation is carried out by various interactions taking place on the membranes of organelles. The membranes themselves contain a multitude of proteins and lipids that mediate these connections and one such class of molecules facilitating these relations are the phospholipids. There are several phospholipids, but the focus of this perspective is on a minor group called the phosphoinositides and specifically, phosphatidylinositol 4,5-bisphosphate (PI-4,5-P2). This phosphoinositide, on intracellular membranes, is largely generated by the non-canonical Type II PIPKs, namely, Phosphotidylinositol-5-phosphate-4-kinases (PI5P4Ks). These evolutionarily conserved enzymes are emerging as key stress response players in cells. Further, PI5P4Ks have been shown to modulate pathways by regulating organelle crosstalk, revealing roles in preserving metabolic homeostasis. Here we will attempt to summarize the functions of the PI5P4Ks and their product PI-4,5-P2 in facilitating inter-organelle communication and how they impact cellular health as well as their relevance to human diseases.

Keywords:  5-P2; PI-4; lipids; metabolism; organelle; peroxisomes; phosphoinositides; phosphotidylinositol-5-phosphate-4-kinases

DOI:  https://doi.org/10.3389/fcell.2021.791758
Mol Biol Rep. 2022 Jan 27.

The impact of DAPK1 and mTORC1 signaling association on autophagy in cancer.

Parvaneh Movahhed, Mohammadreza Saberiyan, Amir Safi, Zahra Arshadi, Faranak Kazerouni, Hossein Teimori.

   BACKGROUND: The autophagy pathway is used by eukaryotic cells to maintain metabolic homeostasis. Autophagy has two functions in cancerous cells which could inhibit tumorigenesis or lead to cancer progression by increasing cell survival and proliferation.
METHODS AND RESULTS: In this review article, Web of Science, PubMed, Scopus, and Google Scholar were searched and summarized published studies to explore the relationship between DAPK1 and mTORC1 signaling association on autophagy in cancer. Autophagy is managed through various proteins including the mTOR, which is two separated structural and functional complexes known as mTORC1 and mTORC2. MTORC1 is an important component of the regulatory pathway affecting numerous cellular functions including proliferation, migration, invasion, and survival. This protein plays a key role in human cancers. The activity level of mTORC1 is regulated by the death-associated protein kinases (DAPks) family, especially DAPK1. In many cancers, DAPK1 acts as a tumor suppressor which can be attributed to its ability to suppress cellular transformation and to inhibit metastasis.
CONCLUSIONS: A deep investigation not only will reveal more about the function of DAPK1 but also might provide insights into novel therapies aimed to modulate the autophagy pathway in cancer and to achieve better cancer therapy.

Keywords:  Autophagy; Cancer; DAPK1; mTORC1

DOI:  https://doi.org/10.1007/s11033-022-07154-1