bims-lymeca Biomed News
on Lysosome metabolism in cancer
Issue of 2023–04–23
ten papers selected by
Harilaos Filippakis, University of New England
  1. Lysosomal lipid peroxidation mediates immunogenic cell death.
  2. An SPNS1-dependent lysosomal lipid transport pathway that enables cell survival under choline limitation.
  3. Role of FLCN Phosphorylation in Insulin-Mediated mTORC1 Activation and Tumorigenesis.
  4. Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1.
  5. Monitoring Calcium Fluxes and Lysosome Exocytosis During Pyroptosis.
  6. Learning the metabolic language of cancer.
  7. Characterization and treatment of gemcitabine- and cisplatin-resistant bladder cancer cells with a pan-RAS inhibitor.
  8. Rab GTPase-regulated phagosome-lysosome fusion is bypassed by micromolar calcium.
  9. Autophagy-Activated Self-reporting Photosensitizer Promoting Cell Mortality in Cancer Starvation Therapy.
  10. Critical role of 6-phosphogluconate dehydrogenase in TAp73-mediated cancer cell proliferation.
  1. J Clin Invest. 2023 Apr 17. pii: e169240. [Epub ahead of print]133(8):
    Lysosomal lipid peroxidation mediates immunogenic cell death.
    Pravin Phadatare, Jayanta Debnath.
      Cancer cells rely on lysosome-dependent degradation to recycle nutrients that serve their energetic and biosynthetic needs. Despite great interest in repurposing the antimalarial hydroxychloroquine as a lysosomal inhibitor in clinical oncology trials, the mechanisms by which hydroxychloroquine and other lysosomal inhibitors induce tumor-cell cytotoxicity remain unclear. In this issue of the JCI, Bhardwaj et al. demonstrate that DC661, a dimeric form of chloroquine that inhibits palmitoyl-protein thioesterase 1 (PPT1), promoted lysosomal lipid peroxidation, resulting in lysosomal membrane permeabilization and tumor cell death. Remarkably, this lysosomal cell death pathway elicited cell-intrinsic immunogenicity and promoted T lymphocyte-mediated tumor cell clearance. The findings provide the mechanistic foundation for the potential combined use of immunotherapy and lysosomal inhibition in clinical trials.
    DOI:  https://doi.org/10.1172/JCI169240
  2. Sci Adv. 2023 04 21. 9(16): eadf8966
    An SPNS1-dependent lysosomal lipid transport pathway that enables cell survival under choline limitation.
    Samantha G Scharenberg, Wentao Dong, Ali Ghoochani, Kwamina Nyame, Roni Levin-Konigsberg, Aswini R Krishnan, Eshaan S Rawat, Kaitlyn Spees, Michael C Bassik, Monther Abu-Remaileh.
      Lysosomes degrade macromolecules and recycle their nutrient content to support cell function and survival. However, the machineries involved in lysosomal recycling of many nutrients remain to be discovered, with a notable example being choline, an essential metabolite liberated via lipid degradation. Here, we engineered metabolic dependency on lysosome-derived choline in pancreatic cancer cells to perform an endolysosome-focused CRISPR-Cas9 screen for genes mediating lysosomal choline recycling. We identified the orphan lysosomal transmembrane protein SPNS1 as critical for cell survival under choline limitation. SPNS1 loss leads to intralysosomal accumulation of lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE). Mechanistically, we reveal that SPNS1 is a proton gradient-dependent transporter of LPC species from the lysosome for their re-esterification into phosphatidylcholine in the cytosol. Last, we establish that LPC efflux by SPNS1 is required for cell survival under choline limitation. Collectively, our work defines a lysosomal phospholipid salvage pathway that is essential under nutrient limitation and, more broadly, provides a robust platform to deorphan lysosomal gene function.
    DOI:  https://doi.org/10.1126/sciadv.adf8966
  3. Adv Sci (Weinh). 2023 Apr 21. e2206826
    Role of FLCN Phosphorylation in Insulin-Mediated mTORC1 Activation and Tumorigenesis.
    Guoyan Wang, Lei Chen, Xinjian Lei, Senlin Qin, Huijun Geng, Yining Zheng, Chao Xia, Junhu Yao, Tong Meng, Lu Deng.
      The amino acid-stimulated Rag GTPase pathway is one of the main pathways that regulate mechanistic target of rapamycin complex 1 (mTORC1) activation and function, but little is known about the effects of growth factors on Rag GTPase-mediated mTORC1 activation. Here, a highly conserved insulin-responsive phosphorylation site on folliculin (FLCN), Ser62, that is phosphorylates by AKT1 is identified and characterized. mTORC2-AKT1 is localized on lysosomes, and RagD-specific recruitment of mTORC2-AKT1 on lysosomes is identified as an essential step in insulin-AKT1-mediated FLCN phosphorylation. Additionally, FLCN phosphorylation inhibits the activity of RagC GTPase and is essential for insulin-induced mTORC1 activation. Functionally, phosphorylated FLCN promotes cell viability and induces autophagy, and also regulates in vivo tumor growth in an mTORC1-dependent manner. Its expression is also positively correlated with mTORC1 activity in colon cancer, clear cell renal cell carcinoma, and chordoma. These results indicate that FLCN is an important intermediate for cross-talk between the amino acid and growth factor pathways. Further, FLCN phosphorylation may be a promising therapeutic target for diseases characterized by mTORC1 dysregulation.
    Keywords:  FLCN phosphorylation; insulin; mTORC1; tumorigenesis
    DOI:  https://doi.org/10.1002/advs.202206826
  4. Science. 2023 Apr 21. 380(6642): eabj5559
    Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1.
    Nazma Malik, Bibiana I Ferreira, Pablo E Hollstein, Stephanie D Curtis, Elijah Trefts, Sammy Weiser Novak, Jingting Yu, Rebecca Gilson, Kristina Hellberg, Lingjing Fang, Arlo Sheridan, Nasun Hah, Gerald S Shadel, Uri Manor, Reuben J Shaw.
      Cells respond to mitochondrial poisons with rapid activation of the adenosine monophosphate-activated protein kinase (AMPK), causing acute metabolic changes through phosphorylation and prolonged adaptation of metabolism through transcriptional effects. Transcription factor EB (TFEB) is a major effector of AMPK that increases expression of lysosome genes in response to energetic stress, but how AMPK activates TFEB remains unresolved. We demonstrate that AMPK directly phosphorylates five conserved serine residues in folliculin-interacting protein 1 (FNIP1), suppressing the function of the folliculin (FLCN)-FNIP1 complex. FNIP1 phosphorylation is required for AMPK to induce nuclear translocation of TFEB and TFEB-dependent increases of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and estrogen-related receptor alpha (ERRα) messenger RNAs. Thus, mitochondrial damage triggers AMPK-FNIP1-dependent nuclear translocation of TFEB, inducing sequential waves of lysosomal and mitochondrial biogenesis.
    DOI:  https://doi.org/10.1126/science.abj5559
  5. Methods Mol Biol. 2023 ;2641 171-178
    Monitoring Calcium Fluxes and Lysosome Exocytosis During Pyroptosis.
    Wendy P Loomis, Tessa Bergsbaken.
      Inflammasome-mediated activation of inflammatory caspases (caspase-1, caspase-4, caspase-5, caspase-11) initiates a cascade of cellular events that lead to proinflammatory cell death, or pyroptosis. Proteolytic cleavage of gasdermin D results in the formation of transmembrane pores that allow the release of mature cytokines IL-1β and IL-18. Gasdermin pores also allow calcium influx through the plasma membrane, triggering the fusion of lysosomal compartments with the cell surface and release of their contents into the extracellular milieu in a process termed lysosome exocytosis. This chapter outlines methods for measuring calcium flux, lysosome exocytosis, and membrane disruption after inflammatory caspase activation.
    Keywords:  Calcium; Gasdermin D; Inflammation; Inflammatory caspases; Lysosome exocytosis; Pyroptosis
    DOI:  https://doi.org/10.1007/978-1-0716-3040-2_14
  6. Nature. 2023 Apr;616(7958): 670-671
    Learning the metabolic language of cancer.
    Minervo Perez, Jordan L Meier.
      
    Keywords:  Cancer; Cell biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-023-01024-x
  7. FEBS Open Bio. 2023 Apr 20.
    Characterization and treatment of gemcitabine- and cisplatin-resistant bladder cancer cells with a pan-RAS inhibitor.
    Hirofumi Yoshino, Seiya Yokoyama, Motoki Tamai, Shunsuke Okamura, Sayaka Iizasa, Takashi Sakaguchi, Yoichi Osako, Satoru Inoguchi, Ryosuke Matsushita, Yasutoshi Yamada, Masayuki Nakagawa, Shuichi Tatarano, Akihide Tanimoto, Hideki Enokida.
      Combination chemotherapy with gemcitabine and cisplatin (GC) is recommended as the primary treatment for advanced bladder cancer (BC). However, the benefits of this approach are limited owing to the acquisition of drug resistance. Here, we found report that gemcitabine-resistant and cisplatin-resistant BCs do not exhibit cross-resistance, and that these BCs exhibit different mRNA patterns, as revealed using RNA sequence analysis. To overcome drug resistance, we used the newly developed pan-RAS inhibitor Compound 3144. Compound 3144 inhibited cell viability through suppression of RAS-dependent signaling in gemcitabine- and cisplatin-resistant BCs. RNA sequencing revealed that several genes and pathways, particularly those related to the cell cycle, were significantly downregulated in Compound 3144-treated BCs. These findings provide insights into potential therapeutic strategies for treating BC.
    Keywords:  RAS; bladder cancer; cisplatin resistance; gemcitabine resistance; pan-RAS inhibitor
    DOI:  https://doi.org/10.1002/2211-5463.13616
  8. J Cell Sci. 2023 Apr 19. pii: jcs.260806. [Epub ahead of print]
    Rab GTPase-regulated phagosome-lysosome fusion is bypassed by micromolar calcium.
    Julia Becker, Ariane Schleinitz, Christina Hermsen, Sabrina Rappold, Paul Saftig, Andreas Jeschke, Albert Haas.
      Several ATP- and cytosol-dependent fusion processes between membranes of the endocytic and exocytic pathways have been biochemically reconstituted. We here present a phagosome-lysosome-fusion reaction driven by micromolar Ca2+ in the absence of ATP and cytosol. Investigating classical and Ca2+-driven fusion (CaFu) side-by-side in vitro, using the same membrane preparations, we show that CaFu is faster than standard fusion (StaFu), leads to larger fusion products, and is not blocked by established inhibitors of StaFu. Approximately 120 µM Ca2+ supports maximal membrane attachment and 15 µM Ca2+ maximal membrane fusion, assigning Ca2+ both a membrane binding and a fusion-promoting activity. StaFu and CaFu are inhibited by a mutant form α-SNAP that does not support SNARE (SNAP receptor) activation, and both are inhibited by a mixture of the cytosolic domains of three cognate Q-SNARE proteins, demonstrating a role of SNAREs in Ca2+-driven membrane merger. CaFu is independent of the calcium-regulated proteins synaptotagmin-7, calmodulin, and annexins A2 and A7. We propose that CaFu corresponds to the last step of phagosome-lysosome fusion, when a raised Ca2+ concentration from the compartment lumen activates SNAREs for fusion.
    Keywords:  Calcium; Lysosome; Membrane fusion; Pathogen; Phagosome; Reconstitution
    DOI:  https://doi.org/10.1242/jcs.260806
  9. Adv Sci (Weinh). 2023 Apr 21. e2301295
    Autophagy-Activated Self-reporting Photosensitizer Promoting Cell Mortality in Cancer Starvation Therapy.
    Ruoyao Zhang, Chen Zhang, Chao Chen, Minggang Tian, Joe H C Chau, Zhao Li, Yuanzhan Yang, Xiaoqiong Li, Ben Zhong Tang.
      Cancer starvation therapy have received continuous attention as an efficient method to fight against wide-spectrum cancer. However, during cancer starvation therapy, the protective autophagy promotes cancer cells survival, compromising the therapeutic effect. Herein, a novel strategy by combination of autophagy-activated fluorescent photosensitizers (PSs) and cancer starvation therapy to realize the controllable and efficient ablation of tumor is conceived. Two dual-emissive self-reporting aggregation-induced emission luminogens (AIEgens), TPAQ and TPAP, with autophagy-activated reactive oxygen species (ROS) generation are prepared to fight against the protective autophagy in cancer starvation therapy. When protective autophagy occurs, a portion of TPAQ and TPAP will translocate from lipid droplets to acidic lysosomes with significant redshift in fluorescence emission and enhanced ROS generation ability. The accumulation of ROS induced by TPAQ-H and TPAP-H causes lysosomal membrane permeabilization (LMP), which further results in cell apoptosis and promotes cell death. In addition, TPAQ and TPAP can enable the real-time self-reporting to cell autophagy and cell death process by observing the change of red-emissive fluorescence signals. Particularly, the efficient ablation of tumor via the combination of cancer starvation therapy and photodynamic therapy (PDT) induced by TPAQ has been successfully confirmed in 3D tumor spheroid chip, suggesting the validation of this strategy.
    Keywords:  3D tumor spheroid chip; autophagy-activated photosensitizer; cancer starvation therapy; dual-emissive self-reporting AIEgen; photodynamic therapy
    DOI:  https://doi.org/10.1002/advs.202301295
  10. Mol Cancer Res. 2023 Apr 18. pii: MCR-22-0814. [Epub ahead of print]
    Critical role of 6-phosphogluconate dehydrogenase in TAp73-mediated cancer cell proliferation.
    Rui Qiao, Mengmeng Wei, Hui Chen, Xianhong Zhang, Jie Zhang, Liyang Gao, Haijun Ma, Yujiong Wang, Le Li.
      Cancer cells frequently alter their metabolism to support biogenesis and proliferation and survive specific metabolic stressors. The glucose-associated pentose phosphate pathway (PPP) is crucial for cancer cell proliferation. In particular, 6-phosphogluconate dehydrogenase (6PGD), the second dehydrogenase in the PPP, catalyzes the decarboxylation of 6-phosphogluconate into ribulose 5-phosphate (Ru5P). However, the mechanisms controlling 6PGD expression in cancer cells remain unclear. Herein, we show that TAp73 increases Ru5P and NADPH production through 6PGD activation to counteract reactive oxygen species and protects cells from apoptosis. Moreover, 6PGD overexpression rescues the proliferation and tumorigenic ability of TAp73-deficient cells. These findings further establish the critical role of TAp73 on glucose metabolism regulation, demonstrating that TAp73 can activate 6PGD expression to support oncogenic cell growth. Implications: By transcriptional upregulation of 6PGD, TAp73 promotes the generation of Ru5P and NADPH, and enhances tumor cell proliferation.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-22-0814
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