bims-lymeca Biomed News
on Lysosome metabolism in cancer
Issue of 2022–05–01
six papers selected by
Harilaos Filippakis, Harvard University
  1. Essential role of lysosomal Ca2+-mediated TFEB activation in mitophagy and functional adaptation of pancreatic β-cells to metabolic stress.
  2. Mutations in V-ATPase in follicular lymphoma activate autophagic flux creating a targetable dependency.
  3. Kinase-independent synthesis of 3-phosphorylated phosphoinositides by a phosphotransferase.
  4. EMT alterations in the solute carrier landscape uncover SLC22A10/A15 imposed vulnerabilities in pancreatic cancer.
  5. Targeting of the glutamine transporter SLC1A5 induces cellular senescence in clear cell renal cell carcinoma.
  6. Effect and mechanism of TFEB on pyroptosis in HK-2 cells induced by high glucose.
  1. Autophagy. 2022 Apr 25.
    Essential role of lysosomal Ca2+-mediated TFEB activation in mitophagy and functional adaptation of pancreatic β-cells to metabolic stress.
    Kihyoun Park, Myung-Shik Lee.
      Although the role of pancreatic β-cell macroautophagy/autophagy is well known, that of β-cell mitophagy is unclear. We investigated the changes of lysosomal Ca2+ by mitochondrial or metabolic stress that can modulate TFEB activation and, additionally, the role of TFEB-induced mitophagy in β-cell function. Mitochondrial or metabolic stress induces mitophagy, which is mediated by lysosomal Ca2+ release, increased cytosolic [Ca2+] and subsequent TFEB activation. Lysosomal Ca2+ release is replenished by ER→lysosome Ca2+ refilling through ER Ca2+ exit channels, which is important for the increase of cytosolic [Ca2+] and mitophagy by mitochondria stressors. High-fat diet (HFD) feeding augments pancreatic β-cell mitophagy, probably as an adaptation to metabolic stress. HFD-induced increase of β-cell mitophagy is reduced by tfeb KO, leading to increased ROS and decreased mitochondrial complex activity or oxygen consumption in tfeb-KO islets. In tfeb Δβ-cell mice, HFD-induced glucose intolerance and β-cell dysfunction are aggravated. Expression of mitophagy receptor genes including Optn or Calcoco2 is increased by mitochondrial or metabolic stressors in a TFEB-dependent manner, likely contributing to increased mitophagy. These results suggest that lysosomal Ca2+ release in conjunction with ER→lysosome Ca2+ refilling is important for TFEB activation and mitophagy induction, which contributes to pancreatic β-cell adaptation to metabolic stress.
    Keywords:  Ca2+; TFEB; lysosome; mitophagy; pancreatic β-cells
    DOI:  https://doi.org/10.1080/15548627.2022.2069956
  2. Autophagy. 2022 Apr 28.
    Mutations in V-ATPase in follicular lymphoma activate autophagic flux creating a targetable dependency.
    Fangyang Wang, Ying Yang, Daniel J Klionsky, Sami N Malek.
      The recent discovery of recurrent gene mutations in chaperones or components of the vacuolar-type H+-translocating ATPase (V-ATPase) in follicular lymphoma (FL) was an unexpected finding. The application of whole exome sequencing and targeted gene re-sequencing has resulted in the identification of mutations in ATP6AP1, ATP6V1B2 and VMA21 in a combined 30% of FL, together constituting a major novel mutated pathway in this disease. Interestingly, no other human hematological malignancy carries these mutations at more than sporadic occurrences, implicating unique aspects of FL biology requiring these mutations. The mutations in ATP6V1B2 and VMA21 through separate mechanisms impair lysosomal V-ATPase activity resulting in an elevated lysosomal pH. The elevated lysosomal pH impairs protein and peptide hydrolysis and associates with reduced cytoplasmic amino acid concentrations resulting in compensatory activation of autophagic flux. The elevated autophagic flux constitutes a survival dependency for FL cells and can be targeted with inhibitors to ULK1 and multiple recently identified cyclin dependent kinase inhibitors. Targeting autophagy alone or in combination with other targeted therapies constitutes a novel therapeutic opportunity for FL patients.
    Keywords:  Autophagy; cancer; disease; therapeutics; tumor
    DOI:  https://doi.org/10.1080/15548627.2022.2071382
  3. Nat Cell Biol. 2022 Apr 28.
    Kinase-independent synthesis of 3-phosphorylated phosphoinositides by a phosphotransferase.
    Glenn F W Walpole, Jonathan Pacheco, Neha Chauhan, Jonathan Clark, Karen E Anderson, Yazan M Abbas, Danielle Brabant-Kirwan, Fernando Montaño-Rendón, Zetao Liu, Hongxian Zhu, John H Brumell, Alexander Deiters, Len R Stephens, Phillip T Hawkins, Gerald R V Hammond, Sergio Grinstein, Gregory D Fairn.
      Despite their low abundance, phosphoinositides play a central role in membrane traffic and signalling. PtdIns(3,4,5)P3 and PtdIns(3,4)P2 are uniquely important, as they promote cell growth, survival and migration. Pathogenic organisms have developed means to subvert phosphoinositide metabolism to promote successful infection and their survival in host organisms. We demonstrate that PtdIns(3,4)P2 is a major product generated in host cells by the effectors of the enteropathogenic bacteria Salmonella and Shigella. Pharmacological, gene silencing and heterologous expression experiments revealed that, remarkably, the biosynthesis of PtdIns(3,4)P2 occurs independently of phosphoinositide 3-kinases. Instead, we found that the Salmonella effector SopB, heretofore believed to be a phosphatase, generates PtdIns(3,4)P2 de novo via a phosphotransferase/phosphoisomerase mechanism. Recombinant SopB is capable of generating PtdIns(3,4,5)P3 and PtdIns(3,4)P2 from PtdIns(4,5)P2 in a cell-free system. Through a remarkable instance of convergent evolution, bacterial effectors acquired the ability to synthesize 3-phosphorylated phosphoinositides by an ATP- and kinase-independent mechanism, thereby subverting host signalling to gain entry and even provoke oncogenic transformation.
    DOI:  https://doi.org/10.1038/s41556-022-00895-y
  4. iScience. 2022 May 20. 25(5): 104193
    EMT alterations in the solute carrier landscape uncover SLC22A10/A15 imposed vulnerabilities in pancreatic cancer.
    Debasis Nayak, Brenna Weadick, Avinash K Persaud, Radhika Raj, Reena Shakya, Junan Li, Moray J Campbell, Rajgopal Govindarajan.
      The involvement of membrane-bound solute carriers (SLCs) in neoplastic transdifferentiation processes is poorly defined. Here, we examined changes in the SLC landscape during epithelial-mesenchymal transition (EMT) of pancreatic cancer cells. We show that two SLCs from the organic anion/cation transporter family, SLC22A10 and SLC22A15, favor EMT via interferon (IFN) α and γ signaling activation of receptor tyrosine kinase-like orphan receptor 1 (ROR1) expression. In addition, SLC22A10 and SLC22A15 allow tumor cell accumulation of glutathione to support EMT via the IFNα/γ-ROR1 axis. Moreover, a pan-SLC22A inhibitor lesinurad reduces EMT-induced metastasis and gemcitabine chemoresistance to prolong survival in mouse models of pancreatic cancer, thus identifying new vulnerabilities for human PDAC.
    Keywords:  Biological sciences; Cancer; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2022.104193
  5. Biochem Biophys Res Commun. 2022 Apr 20. pii: S0006-291X(22)00597-6. [Epub ahead of print]611 99-106
    Targeting of the glutamine transporter SLC1A5 induces cellular senescence in clear cell renal cell carcinoma.
    Issei Kawakami, Hirofumi Yoshino, Wataru Fukumoto, Motoki Tamai, Shunsuke Okamura, Yoichi Osako, Takashi Sakaguchi, Satoru Inoguchi, Ryosuke Matsushita, Yasutoshi Yamada, Shuichi Tatarano, Masayuki Nakagawa, Hideki Enokida.
      In recent years, cancer metabolism has attracted attention as a therapeutic target, and glutamine metabolism is considered one of the most important metabolic processes in cancer. Solute carrier family 1 member 5 (SLC1A5) is a sodium channel that functions as a glutamine transporter. In various cancer types, SLC1A5 gene expression is enhanced, and cancer cell growth is suppressed by inhibition of SLC1A5. However, the involvement of SLC1A5 in clear cell renal cell carcinoma (ccRCC) is unclear. Therefore, in this study, we evaluated the clinical importance of SLC1A5 in ccRCC using The Cancer Genome Atlas database. Our findings confirmed that SLC1A5 was a prognosis factor for poor survival in ccRCC. Furthermore, loss-of-function assays using small interfering RNAs or an SLC1A5 inhibitor (V9302) in human ccRCC cell lines (A498 and Caki1) showed that inhibition of SLC1A5 significantly suppressed tumor growth, invasion, and migration. Additionally, inhibition of SLC1A5 by V9302 in vivo significantly suppressed tumor growth, and the antitumor effects of SLC1A5 inhibition were related to cellular senescence. Our findings may improve our understanding of ccRCC and the development of new treatment strategies for ccRCC.
    Keywords:  Cellular senescence; Glutamine transporter; Renal cell carcinoma; Solute carrier family 1 member 5; V9302
    DOI:  https://doi.org/10.1016/j.bbrc.2022.04.068
  6. Biochem Biophys Res Commun. 2022 Apr 15. pii: S0006-291X(22)00591-5. [Epub ahead of print]610 162-169
    Effect and mechanism of TFEB on pyroptosis in HK-2 cells induced by high glucose.
    Ning Han, Ziqiang Wang, Hongmin Luo, Yanqing Chi, Tao Zhang, Baoxing Wang, Ying Li.
      As a newly discovered way of cell death, pyroptosis has been gradually discovered in acute and chronic kidney disease. Existing studies have shown that reactive oxygen species (ROS) can induce pyroptosis and release a large number of inflammatory mediators, resulting in kidney damage. As a transcription factor, transcription factor EB(TFEB) can regulate mitochondrial energy metabolism, reduce the production of ROS, and reduce the inflammatory damage of vascular endothelial cells. In a high-glucose environment, whether TFEB can regulate oxidative stress in HK-2 cells, thereby reducing pyroptosis, has not yet been studied. This study found that in HK-2 cells, with the prolongation of high concentration glucose stimulation, the expression level of TFEB showed a trend of first increasing and then decreasing; and nuclear translocation of TFEB expression occurred within 24 h. In high-glucose environment, the expression of pyroptosis-related proteins gradually increased over time, while the expression of anti-oxidative stress proteins superoxide dismutase2(SOD2)and NAD(P)H: quinone oxidoreductase 1(NQO1) showed a trend of first increasing and then decreasing. After TFEB was transfected with overexpression plasmid, the expression levels of SOD2 and NQO1 increased significantly, and the expression of pyroptosis-related proteins decreased. Observed under a confocal microscope after Mitosox red staining, the expression of ROS in the TFEB overexpression group decreased. After down-regulating the expression of TFEB, the expression of ROS increased. The research results suggested that in HK-2 cells in the high glucose environment, TFEB may affect the pyroptosis by regulating the expression of antioxidant enzymes SOD2 and NQO1, which provides a new therapeutic idea for the treatment of diabetic nephropathy.
    Keywords:  Diabetic nephropathy; HK-2 cells; Pyroptosis; Reactive oxygen species; TFEB
    DOI:  https://doi.org/10.1016/j.bbrc.2022.04.062
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