bims-lymeca Biomed News
on Lysosome metabolism in cancer
Issue of 2023‒12‒03
six papers selected by
Harilaos Filippakis, University of New England
  1. Targeting the lipid kinase PIKfyve upregulates surface expression of MHC class I to augment cancer immunotherapy.
  2. MITF regulates IDH1 and NNT and drives a transcriptional program protecting cutaneous melanoma from reactive oxygen species.
  3. Membrane transporters in cell physiology, cancer metabolism and drug response.
  4. The immunometabolic ecosystem in cancer.
  5. Interplay of Ca2+ and K+ signals in cell physiology and cancer.
  6. Simvastatin Induces Autophagy and Inhibits Proliferation in Prostate Cancer Cells.
  1. Proc Natl Acad Sci U S A. 2023 Dec 05. 120(49): e2314416120
    Targeting the lipid kinase PIKfyve upregulates surface expression of MHC class I to augment cancer immunotherapy.
    Yi Bao, Yuanyuan Qiao, Jae Eun Choi, Yuping Zhang, Rahul Mannan, Caleb Cheng, Tongchen He, Yang Zheng, Jiali Yu, Mahnoor Gondal, Gabriel Cruz, Sara Grove, Xuhong Cao, Fengyun Su, Rui Wang, Yu Chang, Ilona Kryczek, Marcin Cieslik, Michael D Green, Weiping Zou, Arul M Chinnaiyan.
      Despite the remarkable clinical success of immunotherapies in a subset of cancer patients, many fail to respond to treatment and exhibit resistance. Here, we found that genetic or pharmacologic inhibition of the lipid kinase PIKfyve, a regulator of autophagic flux and lysosomal biogenesis, upregulated surface expression of major histocompatibility complex class I (MHC-I) in cancer cells via impairing autophagic flux, resulting in enhanced cancer cell killing mediated by CD8+ T cells. Genetic depletion or pharmacologic inhibition of PIKfyve elevated tumor-specific MHC-I surface expression, increased intratumoral functional CD8+ T cells, and slowed tumor progression in multiple syngeneic mouse models. Importantly, enhanced antitumor responses by Pikfyve-depletion were CD8+ T cell- and MHC-I-dependent, as CD8+ T cell depletion or B2m knockout rescued tumor growth. Furthermore, PIKfyve inhibition improved response to immune checkpoint blockade (ICB), adoptive cell therapy, and a therapeutic vaccine. High expression of PIKFYVE was also predictive of poor response to ICB and prognostic of poor survival in ICB-treated cohorts. Collectively, our findings show that targeting PIKfyve enhances immunotherapies by elevating surface expression of MHC-I in cancer cells, and PIKfyve inhibitors have potential as agents to increase immunotherapy response in cancer patients.
    Keywords:  MHC class I; PIKfyve; cancer; immunotherapy
    DOI:  https://doi.org/10.1073/pnas.2314416120
  2. bioRxiv. 2023 Nov 14. pii: 2023.11.10.564582. [Epub ahead of print]
    MITF regulates IDH1 and NNT and drives a transcriptional program protecting cutaneous melanoma from reactive oxygen species.
    Elisabeth Roider, Alexandra I T Lakatos, Alicia M McConnell, Poguang Wang, Alina Mueller, Akinori Kawakami, Jennifer Tsoi, Botond L Szabolcs, Anna A Ascsillán, Yusuke Suita, Vivien Igras, Jennifer A Lo, Jennifer J Hsiao, Rebecca Lapides, Dorottya M P Pál, Anna S Lengyel, Alexander Navarini, Arimichi Okazaki, Othon Iliopoulos, István Németh, Thomas G Graeber, Leonard Zon, Roger W Giese, Lajos V Kemeny, David E Fisher.
      Microphthalmia-associated transcription factor (MITF) plays pivotal roles in melanocyte development, function, and melanoma pathogenesis. MITF amplification occurs in melanoma and has been associated with resistance to targeted therapies. Here, we show that MITF regulates a global antioxidant program that increases survival of melanoma cell lines by protecting the cells from reactive oxygen species (ROS)-induced damage. In addition, this redox program is correlated with MITF expression in human melanoma cell lines and patient-derived melanoma samples. Using a zebrafish melanoma model, we show that MITF decreases ROS-mediated DNA damage in vivo . Some of the MITF target genes involved, such as IDH1 and NNT , are regulated through direct MITF binding to canonical enhancer box (E-BOX) sequences proximal to their promoters. Utilizing functional experiments, we demonstrate the role of MITF and its target genes in reducing cytosolic and mitochondrial ROS. Collectively, our data identify MITF as a significant driver of the cellular antioxidant state.One Sentence Summary: MITF promote melanoma survival via increasing ROS tolerance.
    DOI:  https://doi.org/10.1101/2023.11.10.564582
  3. Dis Model Mech. 2023 Nov 01. pii: dmm050404. [Epub ahead of print]16(11):
    Membrane transporters in cell physiology, cancer metabolism and drug response.
    Sara Alam, Emily Doherty, Paula Ortega-Prieto, Julia Arizanova, Louise Fets.
      By controlling the passage of small molecules across lipid bilayers, membrane transporters influence not only the uptake and efflux of nutrients, but also the metabolic state of the cell. With more than 450 members, the Solute Carriers (SLCs) are the largest transporter super-family, clustering into families with different substrate specificities and regulatory properties. Cells of different types are, therefore, able to tailor their transporter expression signatures depending on their metabolic requirements, and the physiological importance of these proteins is illustrated by their mis-regulation in a number of disease states. In cancer, transporter expression is heterogeneous, and the SLC family has been shown to facilitate the accumulation of biomass, influence redox homeostasis, and also mediate metabolic crosstalk with other cell types within the tumour microenvironment. This Review explores the roles of membrane transporters in physiological and malignant settings, and how these roles can affect drug response, through either indirect modulation of sensitivity or the direct transport of small-molecule therapeutic compounds into cells.
    Keywords:  Cancer Metabolism; Drug Uptake; Pharmacology; Transporters
    DOI:  https://doi.org/10.1242/dmm.050404
  4. Nat Immunol. 2023 Dec;24(12): 2008-2020
    The immunometabolic ecosystem in cancer.
    Glenn R Bantug, Christoph Hess.
      Our increased understanding of how key metabolic pathways are activated and regulated in malignant cells has identified metabolic vulnerabilities of cancers. Translating this insight to the clinics, however, has proved challenging. Roadblocks limiting efficacy of drugs targeting cancer metabolism may lie in the nature of the metabolic ecosystem of tumors. The exchange of metabolites and growth factors between cancer cells and nonmalignant tumor-resident cells is essential for tumor growth and evolution, as well as the development of an immunosuppressive microenvironment. In this Review, we will examine the metabolic interplay between tumor-resident cells and how targeted inhibition of specific metabolic enzymes in malignant cells could elicit pro-tumorigenic effects in non-transformed tumor-resident cells and inhibit the function of tumor-specific T cells. To improve the efficacy of metabolism-targeted anticancer strategies, a holistic approach that considers the effect of metabolic inhibitors on major tumor-resident cell populations is needed.
    DOI:  https://doi.org/10.1038/s41590-023-01675-y
  5. Curr Top Membr. 2023 ;pii: S1063-5823(23)00027-3. [Epub ahead of print]92 15-46
    Interplay of Ca2+ and K+ signals in cell physiology and cancer.
    Andrea Becchetti.
      The cytoplasmic Ca2+ concentration and the activity of K+ channels on the plasma membrane regulate cellular processes ranging from mitosis to oriented migration. The interplay between Ca2+ and K+ signals is intricate, and different cell types rely on peculiar cellular mechanisms. Derangement of these mechanisms accompanies the neoplastic progression. The calcium signals modulated by voltage-gated (KV) and calcium-dependent (KCa) K+ channel activity regulate progression of the cell division cycle, the release of growth factors, apoptosis, cell motility and migration. Moreover, KV channels regulate the cell response to the local microenvironment by assembling with cell adhesion and growth factor receptors. This chapter summarizes the pathophysiological roles of Ca2+ and K+ fluxes in normal and cancer cells, by concentrating on several biological systems in which these functions have been studied in depth, such as early embryos, mammalian cell lines, T lymphocytes, gliomas and colorectal cancer cells. A full understanding of the underlying mechanisms will offer a comprehensive view of the ion channel implication in cancer biology and suggest potential pharmacological targets for novel therapeutic approaches in oncology.
    Keywords:  CRAC; Cell cycle; Cisplatin; Colorectal; Glioma; Integrin; KCa; KV1.3; KV11; Lymphocyte
    DOI:  https://doi.org/10.1016/bs.ctm.2023.09.006
  6. Anticancer Res. 2023 Dec;43(12): 5377-5386
    Simvastatin Induces Autophagy and Inhibits Proliferation in Prostate Cancer Cells.
    Yoshiyuki Miyazawa, Yoshitaka Sekine, Daisuke Oka, Shun Nakazawa, Yusuke Tsuji, Hiroshi Nakayama, Kazuhiro Suzuki.
      BACKGROUND/AIM: Statin has recently been studied for its effects on inducing cell death and inhibiting metastasis. Nevertheless, the precise mechanism of its anti-tumor effect is not yet fully understood. We conducted research on statin as a novel treatment for castration-resistant prostate cancer (CRPC). This study focused on autophagy in prostate cancer cells and assessed the effects of simvastatin.MATERIALS AND METHODS: After administering simvastatin to PC-3 cells, we conducted a microarray analysis. Simvastatin was administered to prostate cancer cell lines (PC-3, LNCaP-LA; cultured under androgen-depleted conditions, DU145, 22RV1), and the tumor proliferation inhibition was evaluated using the MTS assay and cell count. Autophagy was measured by observing autophagosome staining under a fluorescence microscope and quantifying LC-3 protein using western blot. We also investigated the effects of rapamycin, an autophagy inducer, and chloroquine as an inhibitor.
    RESULTS: Simvastatin demonstrated a significant concentration-dependent growth inhibition effect on prostate cell lines. Moreover, a significant increase in autophagy was observed in all cell lines following simvastatin administration. When we administered simvastatin with rapamycin at a concentration that did not show a tumor growth inhibitory effect, it significantly enhanced autophagy induction compared to simvastatin alone, and also significantly enhanced the growth inhibition effect on PC-3 cells.
    CONCLUSION: Simvastatin induced autophagy and inhibited the proliferation of prostate cancer cell lines. The combination of simvastatin and rapamycin significantly induced autophagy and enhanced the inhibitory effect of simvastatin on proliferation. This mechanism may serve as a novel therapeutic target.
    Keywords:  Prostate cancer; autophagy; rapamycin; statin
    DOI:  https://doi.org/10.21873/anticanres.16741
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