bims-lymeca 2022-05-29 papers

bims-lymeca

Biomed News

on Lysosome metabolism in cancer

Issue of 2022–05–29
seven papers selected by
Harilaos Filippakis, University of New England

Overexpression of V-ATPase B2 attenuates lung injury/fibrosis by stabilizing lysosomal membrane permeabilization and increasing collagen degradation.
SERTAD1 Sensitizes Breast Cancer Cells to Doxorubicin and Promotes Lysosomal Protein Biosynthesis.
Lysosomal lipid switch sensitises to nutrient deprivation and mTOR targeting in pancreatic cancer.
Rendezvous with PI(3,5)P2 - A rapalog gets caught opening TRPML1.
Lyso-IP: Uncovering Pathogenic Mechanisms of Lysosomal Dysfunction.
Developing dietary interventions as therapy for cancer.
Phosphatidylinositol Phosphates Modulate Interactions between the StarD4 Sterol Trafficking Protein and Lipid Membranes.

Exp Mol Med. 2022 May 27.

Overexpression of V-ATPase B2 attenuates lung injury/fibrosis by stabilizing lysosomal membrane permeabilization and increasing collagen degradation.

Jong-Uk Lee, Jisu Hong, Hyesun Shin, Chnag-Beom Ryu, Sung-Woo Park, Sung Hwan Jeong.

Excessive oxidative stress causes lysosomal membrane permeabilization (LMP), which leads to cell death. Vacuolar ATPase (V-ATPase) is the enzyme responsible for pumping H+ into the cytosol and thus maintaining intracellular pH. Previously, we reported that V-ATPase B2 subunit expression is upregulated in the TiO2-exposed lung epithelium. We investigated the role of the lysosomal V-ATPase B2 subunit in oxidative stress-induced alveolar epithelial cell death and in an experimental lung injury/fibrosis model. Overexpression of V-ATPase B2 increased lysosomal pH and lysosomal activities in the cells. In the presence of H2O2, overexpression of V-ATPase B2 increased survival, and silencing of V-ATPase B2 dramatically increased cell death. Overexpression of V-ATPase B2 diminished H2O2-triggered LMP, as evidenced by a reduction in acridine orange staining and leakage of cathepsin D from the lysosome to the cytoplasm. In addition, V-ATPase B2-overexpressing macrophages exhibited significantly enhanced uptake and degradation of collagen. V-ATPase B2-overexpressing transgenic mice showed significant inhibition of the bleomycin-induced increases in lung inflammation and fibrosis. We conclude that V-ATPase B2 is critical for maintaining lysosomal activities against excessive oxidative stress by stabilizing LMP. Our findings reveal a previously unknown role of this V-ATPase subunit in a lung injury and fibrosis model.

DOI: https://doi.org/10.1038/s12276-022-00776-2
Biomedicines. 2022 May 17. pii: 1148. [Epub ahead of print]10(5):

SERTAD1 Sensitizes Breast Cancer Cells to Doxorubicin and Promotes Lysosomal Protein Biosynthesis.

Hai Anh Nguyen, Son Hai Vu, Samil Jung, Beom Suk Lee, Thi Ngoc Quynh Nguyen, Hyojeong Lee, Hye-Gyeong Lee, Davaajargal Myagmarjav, Taeyeon Jo, Yeongseon Choi, Myeong-Sok Lee.

  Acquired chemoresistance of tumor cells is an unwanted consequence of cancer treatment. Overcoming chemoresistance is particularly important for efficiently improving cancer therapies. Here, using multiple lines of evidence, we report the suppressive role of SERTAD1 in apoptosis/anoikis. Among various breast cancer cell lines, higher SERTAD1 expression was found in MCF7 and MDA-MB-231 in suspension than in adherent cell culture. We revealed an unexpected phenomenon that different types of cell deaths were induced in response to different doses of doxorubicin (Dox) in breast cancer cells, presumably via lysosomal membrane permeabilization. A low dose of Dox highly activated autophagy, while a high dose of the chemotherapy induced apoptosis. Inhibition of SERTAD1 promoted the sensitivity of breast cancer cells to Dox and paclitaxel, leading to a significant reduction in tumor volumes of xenograft mice. Simultaneously targeting cancer cells with Dox and autophagy inhibition successfully induced higher apoptosis/anoikis. The novel role of SERTAD1 in maintaining cellular homeostasis has also been suggested in which lysosomal contents, including LAMP1, LAMP2, CTSB, and CTSD, were reduced in SERTAD1-deficient cells.

Keywords:  SERTAD1; anoikis; anti-cancer drugs; autophagy; breast cancer; lysosomal biogenesis

DOI:  https://doi.org/10.3390/biomedicines10051148
Gut. 2022 May 27. pii: gutjnl-2021-325117. [Epub ahead of print]

Lysosomal lipid switch sensitises to nutrient deprivation and mTOR targeting in pancreatic cancer.

Maria Chiara De Santis, Luca Gozzelino, Jean Piero Margaria, Andrea Costamagna, Edoardo Ratto, Federico Gulluni, Enza Di Gregorio, Erica Mina, Nicla Lorito, Marina Bacci, Rossano Lattanzio, Gianluca Sala, Paola Cappello, Francesco Novelli, Elisa Giovannetti, Caterina Vicentini, Silvia Andreani, Pietro Delfino, Vincenzo Corbo, Aldo Scarpa, Paolo Ettore Porporato, Andrea Morandi, Emilio Hirsch, Miriam Martini.

   OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with limited therapeutic options. However, metabolic adaptation to the harsh PDAC environment can expose liabilities useful for therapy. Targeting the key metabolic regulator mechanistic target of rapamycin complex 1 (mTORC1) and its downstream pathway shows efficacy only in subsets of patients but gene modifiers maximising response remain to be identified.
DESIGN: Three independent cohorts of PDAC patients were studied to correlate PI3K-C2γ protein abundance with disease outcome. Mechanisms were then studied in mouse (KPC mice) and cellular models of PDAC, in presence or absence of PI3K-C2γ (WT or KO). PI3K-C2γ-dependent metabolic rewiring and its impact on mTORC1 regulation were assessed in conditions of limiting glutamine availability. Finally, effects of a combination therapy targeting mTORC1 and glutamine metabolism were studied in WT and KO PDAC cells and preclinical models.
RESULTS: PI3K-C2γ expression was reduced in about 30% of PDAC cases and was associated with an aggressive phenotype. Similarly, loss of PI3K-C2γ in KPC mice enhanced tumour development and progression. The increased aggressiveness of tumours lacking PI3K-C2γ correlated with hyperactivation of mTORC1 pathway and glutamine metabolism rewiring to support lipid synthesis. PI3K-C2γ-KO tumours failed to adapt to metabolic stress induced by glutamine depletion, resulting in cell death.
CONCLUSION: Loss of PI3K-C2γ prevents mTOR inactivation and triggers tumour vulnerability to RAD001 (mTOR inhibitor) and BPTES/CB-839 (glutaminase inhibitors). Therefore, these results might open the way to personalised treatments in PDAC with PI3K-C2γ loss.

Keywords:  AMINO ACIDS; CELL BIOLOGY; LIPID METABOLISM; PANCREATIC CANCER; SIGNAL TRANSDUCTION

DOI:  https://doi.org/10.1136/gutjnl-2021-325117
Cell Calcium. 2022 May 14. pii: S0143-4160(22)00071-9. [Epub ahead of print]105 102597

Rendezvous with PI(3,5)P2 - A rapalog gets caught opening TRPML1.

Taufiq Rahman, Sandip Patel.

  TRPML1 is an endolysosomally-expressed cation channel, activated physiologically by PI(3,5)P2 and by several synthetic agonists including rapamycin. New high resolution cryo-EM- structures of TRPML1 bound to both PI(3,5)P2 and temsirolimus - a rapamycin analog provides molecular insight into how the channel integrates two agonists that bind to distal sites but act cooperatively.

Keywords:  Allosteric; Ca(2+) channels; Lysosome; PI(3,5)P(2); Rapamycin; TRPML1; Temsirolimus

DOI:  https://doi.org/10.1016/j.ceca.2022.102597
Biomolecules. 2022 Apr 21. pii: 616. [Epub ahead of print]12(5):

Lyso-IP: Uncovering Pathogenic Mechanisms of Lysosomal Dysfunction.

Chase Chen, Ellen Sidransky, Yu Chen.

  Lysosomes are ubiquitous membrane-bound organelles found in all eukaryotic cells. Outside of their well-known degradative function, lysosomes are integral in maintaining cellular homeostasis. Growing evidence has shown that lysosomal dysfunction plays an important role not only in the rare group of lysosomal storage diseases but also in a host of others, including common neurodegenerative disorders, such as Alzheimer disease and Parkinson disease. New technological advances have significantly increased our ability to rapidly isolate lysosomes from cells in recent years. The development of the Lyso-IP approach and similar methods now allow for lysosomal purification within ten minutes. Multiple studies using the Lyso-IP approach have revealed novel insights into the pathogenic mechanisms of lysosomal disorders, including Niemann-Pick type C disease, showing the immense potential for this technique. Future applications of rapid lysosomal isolation techniques are likely to greatly enhance our understanding of lysosomal dysfunction in rare and common neurodegeneration causes.

Keywords:  Niemann-Pick type C; lysosome isolation; lysosomes

DOI:  https://doi.org/10.3390/biom12050616
Nat Rev Cancer. 2022 May 25.

Developing dietary interventions as therapy for cancer.

Samuel R Taylor, John N Falcone, Lewis C Cantley, Marcus D Goncalves.

Cancer cells acquire distinct metabolic preferences based on their tissue of origin, genetic alterations and degree of interaction with systemic hormones and metabolites. These adaptations support the increased nutrient demand required for increased growth and proliferation. Diet is the major source of nutrients for tumours, yet dietary interventions lack robust evidence and are rarely prescribed by clinicians for the treatment of cancer. Well-controlled diet studies in patients with cancer are rare, and existing studies have been limited by nonspecific enrolment criteria that inappropriately grouped together subjects with disparate tumour and host metabolic profiles. This imprecision may have masked the efficacy of the intervention for appropriate candidates. Here, we review the metabolic alterations and key vulnerabilities that occur across multiple types of cancer. We describe how these vulnerabilities could potentially be targeted using dietary therapies including energy or macronutrient restriction and intermittent fasting regimens. We also discuss recent trials that highlight how dietary strategies may be combined with pharmacological therapies to treat some cancers, potentially ushering a path towards precision nutrition for cancer.

DOI: https://doi.org/10.1038/s41568-022-00485-y
J Biol Chem. 2022 May 20. pii: S0021-9258(22)00498-7. [Epub ahead of print] 102058

Phosphatidylinositol Phosphates Modulate Interactions between the StarD4 Sterol Trafficking Protein and Lipid Membranes.

Xiaoxue Zhang, Hengyi Xie, David Iaea, George Khelashvili, Harel Weinstein, Frederick R Maxfield.

  There is substantial evidence for extensive non-vesicular sterol transport in cells. For example, lipid transfer by the steroidogenic acute regulator-related proteins (StarD) containing a StarT domain has been shown to involve several pathways of non-vesicular trafficking. Among the soluble StarT domain containing proteins, StarD4 is expressed in most tissues and has been shown to be an effective sterol transfer protein. However, it was unclear whether the lipid composition of donor or acceptor membranes played a role in modulating StarD4-mediated transport. Here we used fluorescence-based assays to demonstrate a phosphatidylinositol phosphate (PIP)-selective mechanism by which StarD4 can preferentially extract sterol from liposome membranes containing certain PIPs (especially, PI(4,5)P2 and to a lesser degree PI(3,5)P2). Monophosphorylated PIPs and other anionic lipids had a smaller effect on sterol transport. This enhancement of transport was less effective when the same PIPs were present in the acceptor membranes. Furthermore, using molecular dynamics simulations, we mapped the key interaction sites of StarD4 with PIP-containing membranes and identified residues that are important for this interaction and for accelerated sterol transport activity. We show that StarD4 recognizes membrane-specific PIPs through specific interaction with the geometry of the PIP head group as well as the surrounding membrane environment. Finally, we also observed that StarD4 can deform membranes upon longer incubations. Taken together, these results suggest a mechanism by which phosphatidylinositol phosphates modulate cholesterol transfer activity via StarD4.

Keywords:  cholesterol‐binding protein; computer modeling; electron microscopy (EM); lipid transport; liposome; membrane lipid

DOI:  https://doi.org/10.1016/j.jbc.2022.102058