bims-lymeca Biomed News
on Lysosome metabolism in cancer
Issue of 2023–08–27
ten papers selected by
Harilaos Filippakis, University of New England
  1. The CTNS-MTORC1 axis couples lysosomal cystine to epithelial cell fate decisions and is a targetable pathway in cystinosis.
  2. Real-Time Monitoring of Lysosomal Membrane Permeabilization Using Acridine Orange.
  3. The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease.
  4. Fatty acid availability controls autophagy and associated cell functions.
  5. Clinical Significance of Carnitine in the Treatment of Cancer: From Traffic to the Regulation.
  6. MAPK13 stabilization via m6A mRNA modification limits anti-cancer efficacy of rapamycin.
  7. Neuronal atg1 Coordinates Autophagy Induction and Physiological Adaptations to Balance mTORC1 Signalling.
  8. Targeting SphK1/2 by SKI-178 inhibits prostate cancer cell growth.
  9. A pan-cancer analysis of lipid metabolic alterations in primary and metastatic cancers.
  10. Discovery of a First-in-Class Degrader for the Lipid Kinase PIKfyve.
  1. Autophagy. 2023 Aug 24. 1-3
    The CTNS-MTORC1 axis couples lysosomal cystine to epithelial cell fate decisions and is a targetable pathway in cystinosis.
    Alessandro Luciani, Olivier Devuyst.
      Differentiation and fate decisions are critical for the epithelial cells lining the proximal tubule (PT) of the kidney, but the signals involved remain unknown. Defective cystine mobilization from lysosomes through CTNS (cystinosin, lysosomal cystine transporter), which is mutated in cystinosis, triggers the dedifferentiation and dysfunction of the PT cells, causing kidney disease and severe metabolic complications. Using preclinical models and physiologically relevant cellular systems, along with functional assays and a generative artificial intelligence (AI)-powered engine, we found that cystine storage imparted by CTNS deficiency stimulates Ragulator-RRAG GTPase-dependent recruitment of MTORC1 and its constitutive activation. In turn, this diverts the catabolic trajectories and differentiating states of PT cells toward growth and proliferation, disrupting homeostasis and their specialized functions. Therapeutic MTORC1 inhibition by using low doses of rapamycin corrects lysosome function and differentiation downstream of cystine storage and ameliorates PT dysfunction in preclinical models of cystinosis. These discoveries suggest that cystine may act as a lysosomal fasting signal that tailors MTORC1 signaling to direct fate decisions in the kidney PT epithelium, highlighting novel therapeutic paradigms for cystinosis and other lysosome-related disorders.
    Keywords:  autophagy; chronic kidney disease; cystinosis; drug repurposing; lysosome; nutrient sensing
    DOI:  https://doi.org/10.1080/15548627.2023.2250165
  2. Methods Protoc. 2023 Aug 09. pii: 72. [Epub ahead of print]6(4):
    Real-Time Monitoring of Lysosomal Membrane Permeabilization Using Acridine Orange.
    Ida Eriksson, Linda Vainikka, Hans Lennart Persson, Karin Öllinger.
      Loss of lysosomal membrane integrity results in leakage of lysosomal hydrolases to the cytosol which might harm cell function and induce cell death. Destabilization of lysosomes often precede apoptotic or necrotic cell death and occur during both physiological and pathological conditions. The weak base acridine orange readily enters cells and accumulates in the acidic environment of lysosomes. Vital staining with acridine orange is a well-proven technique to observe lysosomal destabilization using fluorescence microscopy and flow cytometry. These analyses are, however, time consuming and only adapted for discrete time points, which make them unsuitable for large-scale approaches. Therefore, we have developed a time-saving, high-throughput microplate reader-based method to follow destabilization of the lysosomal membrane in real-time using acridine orange. This protocol can easily be adopted for patient samples since the number of cells per sample is low and the time for analysis is short.
    Keywords:  acridine orange; high throughput; lysosomal membrane permeabilization; lysosome
    DOI:  https://doi.org/10.3390/mps6040072
  3. Nat Rev Mol Cell Biol. 2023 Aug 23.
    The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease.
    Claire Goul, Roberta Peruzzo, Roberto Zoncu.
      The Ser/Thr kinase mechanistic target of rapamycin (mTOR) is a central regulator of cellular metabolism. As part of mTOR complex 1 (mTORC1), mTOR integrates signals such as the levels of nutrients, growth factors, energy sources and oxygen, and triggers responses that either boost anabolism or suppress catabolism. mTORC1 signalling has wide-ranging consequences for the growth and homeostasis of key tissues and organs, and its dysregulated activity promotes cancer, type 2 diabetes, neurodegeneration and other age-related disorders. How mTORC1 integrates numerous upstream cues and translates them into specific downstream responses is an outstanding question with major implications for our understanding of physiology and disease mechanisms. In this Review, we discuss recent structural and functional insights into the molecular architecture of mTORC1 and its lysosomal partners, which have greatly increased our mechanistic understanding of nutrient-dependent mTORC1 regulation. We also discuss the emerging involvement of aberrant nutrient-mTORC1 signalling in multiple diseases.
    DOI:  https://doi.org/10.1038/s41580-023-00641-8
  4. Autophagy. 2023 Aug 21. 1-2
    Fatty acid availability controls autophagy and associated cell functions.
    Leslie A Rowland, Michael P Czech.
      Macroautophagy/autophagy requires enormous membrane expansions during concerted actions of transient autophagic vesicles and lysosomes, yet the source of the membrane lipids is poorly understood. Recent work in adipocytes has now pinpointed the de novo lipogenesis pathway as the preferred source of fatty acids for phospholipid in autophagic membrane synthesis, as loss of FASN (fatty acid synthase) disrupts autophagic flux and lysosome function in vivo and in vitro. These data indicate fatty acid synthesis channels lipid for membrane expansions, whereas fatty acids from circulating lipoproteins provide for adipose lipid storage. Importantly, autophagy blockade upon loss of fatty acids promotes a strong thermogenic phenotype in adipocytes, another striking example whereby autophagy controls cell behavior.
    Keywords:  Adipocyte; FASN; autophagosome; lipogenesis; lipophagy; p62
    DOI:  https://doi.org/10.1080/15548627.2023.2246357
  5. Oxid Med Cell Longev. 2023 ;2023 9328344
    Clinical Significance of Carnitine in the Treatment of Cancer: From Traffic to the Regulation.
    Raheleh Farahzadi, Mohammad Saeid Hejazi, Ommoleila Molavi, Elahe Pishgahzadeh, Soheila Montazersaheb, Sevda Jafari.
      Metabolic reprogramming is a common hallmark of cancer cells. Cancer cells exhibit metabolic flexibility to maintain high proliferation and survival rates. In other words, adaptation of cellular demand is essential for tumorigenesis, since a diverse supply of nutrients is required to accommodate tumor growth and progression. Diversity of carbon substrates fueling cancer cells indicate metabolic heterogeneity, even in tumors sharing the same clinical diagnosis. In addition to the alteration of glucose and amino acid metabolism in cancer cells, there is evidence that cancer cells can alter lipid metabolism. Some tumors rely on fatty acid oxidation (FAO) as the primary energy source; hence, cancer cells overexpress the enzymes involved in FAO. Carnitine is an essential cofactor in the lipid metabolic pathways. It is crucial in facilitating the transport of long-chain fatty acids into the mitochondria for β-oxidation. This role and others played by carnitine, especially its antioxidant function in cellular processes, emphasize the fine regulation of carnitine traffic within tissues and subcellular compartments. The biological activity of carnitine is orchestrated by specific membrane transporters that mediate the transfer of carnitine and its derivatives across the cell membrane. The concerted function of carnitine transporters creates a collaborative network that is relevant to metabolic reprogramming in cancer cells. Here, the molecular mechanisms relevant to the role and expression of carnitine transporters are discussed, providing insights into cancer treatment.
    DOI:  https://doi.org/10.1155/2023/9328344
  6. J Biol Chem. 2023 Aug 18. pii: S0021-9258(23)02203-2. [Epub ahead of print] 105175
    MAPK13 stabilization via m6A mRNA modification limits anti-cancer efficacy of rapamycin.
    Joohwan Kim, Yujin Chun, Cuauhtemoc B Ramirez, Lauren A Hoffner, Sunhee Jung, Ki-Hong Jang, Varvara I Rubtsova, Cholsoon Jang, Gina Lee.
      N6-adenosine methylation (m6A) is the most abundant mRNA modification that controls gene expression through diverse mechanisms. Accordingly, m6A-dependent regulation of oncogenes and tumor suppressors contributes to tumor development. However, the role of m6A-mediated gene regulation upon drug treatment or resistance is poorly understood. Here, we report that m6A modification of mitogen-activated protein kinase 13 (MAPK13) mRNA determines the sensitivity of cancer cells to the mechanistic target of rapamycin complex 1 (mTORC1)-targeting agent rapamycin. mTORC1 induces m6A modification of MAPK13 mRNA at its 3' untranslated region (3'UTR) through the methyltransferase-like 3 (METTL3)-METTL14-Wilms' tumor 1-associating protein (WTAP) methyltransferase complex, facilitating its mRNA degradation via an m6A reader protein YTH domain family protein 2 (YTHDF2). Rapamycin blunts this process and stabilizes MAPK13. On the other hand, genetic or pharmacological inhibition of MAPK13 enhances rapamycin's anti-cancer effects, which suggests that MAPK13 confers a pro-growth signal upon rapamycin treatment, thereby limiting rapamycin efficacy. Together, our data indicate that rapamycin-mediated MAPK13 mRNA stabilization underlies drug resistance, and it should be considered as a promising therapeutic target to sensitize cancer cells to rapamycin.
    Keywords:  MAPK13; RNA modification; RNA stability; Rapamycin; m(6)A; mTORC1; p38
    DOI:  https://doi.org/10.1016/j.jbc.2023.105175
  7. Cells. 2023 Aug 08. pii: 2024. [Epub ahead of print]12(16):
    Neuronal atg1 Coordinates Autophagy Induction and Physiological Adaptations to Balance mTORC1 Signalling.
    Athanasios Metaxakis, Michail Pavlidis, Nektarios Tavernarakis.
      The mTORC1 nutrient-sensing pathway integrates metabolic and endocrine signals into the brain to evoke physiological responses to food deprivation, such as autophagy. Nevertheless, the impact of neuronal mTORC1 activity on neuronal circuits and organismal metabolism remains obscure. Here, we show that mTORC1 inhibition acutely perturbs serotonergic neurotransmission via proteostatic alterations evoked by the autophagy inducer atg1. Neuronal ATG1 alters the intracellular localization of the serotonin transporter, which increases the extracellular serotonin and stimulates the 5HTR7 postsynaptic receptor. 5HTR7 enhances food-searching behaviour and ecdysone-induced catabolism in Drosophila. Along similar lines, the pharmacological inhibition of mTORC1 in zebrafish also stimulates food-searching behaviour via serotonergic activity. These effects occur in parallel with neuronal autophagy induction, irrespective of the autophagic activity and the protein synthesis reduction. In addition, ectopic neuronal atg1 expression enhances catabolism via insulin pathway downregulation, impedes peptidergic secretion, and activates non-cell autonomous cAMP/PKA. The above exert diverse systemic effects on organismal metabolism, development, melanisation, and longevity. We conclude that neuronal atg1 aligns neuronal autophagy induction with distinct physiological modulations, to orchestrate a coordinated physiological response against reduced mTORC1 activity.
    Keywords:  5HTR7 receptor; ATG1; ageing; autophagy; behaviour; cAMP/PKA; ecdysone; longevity; mTORC1; metabolism; serotonin transporter
    DOI:  https://doi.org/10.3390/cells12162024
  8. Cell Death Dis. 2023 08 21. 14(8): 537
    Targeting SphK1/2 by SKI-178 inhibits prostate cancer cell growth.
    Lu Jin, Jin Zhu, Linya Yao, Gang Shen, Bo-Xin Xue, Wei Tao.
      Sphingosine kinases (SphK), including SphK1 and SphK2, are important enzymes promoting progression of prostate cancer. SKI-178 is a novel and highly potent SphK1/2 dual inhibitor. We here tested the potential anti-prostate cancer cell activity of SKI-178. Bioinformatics analyses and results from local tissues demonstrated that that both SphK1 and SphK2 are upregulated in human prostate cancer tissues. Ectopic overexpression of SphK1 and SphK2, by lentiviral constructs, promoted primary prostate cancer cell proliferation and migration. In primary human prostate cancer cells and immortalized cell lines, SKI-178 potently inhibited cell viability, proliferation, cell cycle progression and cell migration, causing robust cell death and apoptosis. SKI-178 impaired mitochondrial functions, causing mitochondrial depolarization, reactive oxygen species production and ATP depletion.SKI-178 potently inhibited SphK activity and induced ceramide production, without affecting SphK1/2 expression in prostate cancer cells. Further, SKI-178 inhibited Akt-mTOR activation and induced JNK activation in prostate cancer cells. Contrarily, a constitutively-active Akt1 construct or the pharmacological JNK inhibitors attenuated SKI-178-induced cytotoxicity in prostate cancer cells. In vivo, daily intraperitoneal injection of a single dose of SKI-178 potently inhibited PC-3 xenograft growth in nude mice. SphK inhibition, ceramide production, ATP depletion and lipid peroxidation as well as Akt-mTOR inactivation and JNK activation were detected in PC-3 xenograft tissues with SKI-178 administration. Together, targeting SphK1/2 by SKI-178 potently inhibited prostate cancer cell growth in vitro and in vivo.
    DOI:  https://doi.org/10.1038/s41419-023-06023-4
  9. Sci Rep. 2023 Aug 23. 13(1): 13810
    A pan-cancer analysis of lipid metabolic alterations in primary and metastatic cancers.
    Guoqing Liu, Yan Yang, Xuejia Kang, Hao Xu, Jing Ai, Min Cao, Guojun Liu.
      Metabolic reprogramming is a hallmark of cancers, but pan-cancer level roles of lipid metabolism in cancer development are remains poorly understood. We investigated the possible roles of lipid metabolic genes (LMGs) in 14 cancer types. The results indicate that: (1) there is strong evidence for increased lipid metabolism in THCA and KICH. (2) Although the overall levels of lipid metabolic processes are down-regulated in some cancer types, fatty acid synthase activity and fatty acid elongation are moderately up-regulated in more than half of the cancer types. Cholesterol synthesis is up-regulated in five cancers including KICH, BLCA, COAD, BRCA, UCEC, and THCA. (3) The catabolism of cholesterols, triglycerides and fatty acids is repressed in most cancers, but a specific form of lipid degradation, lipophagy, is activated in THCA and KICH. (4) Lipid storage is enhanced in in kidney cancers and thyroid cancer. (5) Similarly to primary tumors, metastatic tumors tend to up-regulate biosynthetic processes of diverse lipids, but down-regulate lipid catabolic processes, except lipophagy. (6) The frequently mutated lipid metabolic genes are not key LMGs. (7) We established a LMG-based model for predicting cancer prognosis. Our results are helpful in expanding our understanding of the role of lipid metabolism in cancer.
    DOI:  https://doi.org/10.1038/s41598-023-41107-3
  10. J Med Chem. 2023 Aug 21.
    Discovery of a First-in-Class Degrader for the Lipid Kinase PIKfyve.
    Chungen Li, Yuanyuan Qiao, Xia Jiang, Lianchao Liu, Yang Zheng, Yudi Qiu, Caleb Cheng, Fengtao Zhou, Yang Zhou, Weixue Huang, Xiaomei Ren, Yuzhuo Wang, Zhen Wang, Arul M Chinnaiyan, Ke Ding.
      The phosphoinositide kinase PIKfyve has emerged as a new potential therapeutic target in various cancers. However, limited clinical progress has been achieved with PIKfyve inhibitors. Here, we report the discovery of a first-in-class PIKfyve degrader 12d (PIK5-12d) by employing the proteolysis-targeting chimera approach. PIK5-12d potently degraded PIKfyve protein with a DC50 value of 1.48 nM and a Dmax value of 97.7% in prostate cancer VCaP cells. Mechanistic studies revealed that it selectively induced PIKfyve degradation in a VHL- and proteasome-dependent manner. PIKfyve degradation by PIK5-12d caused massive cytoplasmic vacuolization and blocked autophagic flux in multiple prostate cancer cell lines. Importantly, PIK5-12d was more effective in suppressing the growth of prostate cancer cells than the parent inhibitor and exerted prolonged inhibition of downstream signaling. Further, intraperitoneal administration of PIK5-12d exhibited potent PIKfyve degradation and suppressed tumor proliferation in vivo. Overall, PIK5-12d is a valuable chemical tool for exploring PIKfyve-based targeted therapy.
    DOI:  https://doi.org/10.1021/acs.jmedchem.3c00912
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