bims-pimaco Biomed News
on PI3K and MAPK signalling in colorectal cancer
Issue of 2023‒09‒17
seven papers selected by
Lucas B. Zeiger, Beatson Institute for Cancer Research
  1. Proteostasis Network Modulation Promotes Resistance to KRAS Inhibitors.
  2. Differential Structural Dynamics Exist between Wild-type and Oncogenic K-Ras.
  3. Phosphorylation at tyrosine 317 and 508 are crucial for PIK3CA/p110α to promote CRC tumorigenesis.
  4. Continuous sensing of nutrients and growth factors by the mTORC1-TFEB axis.
  5. Codependencies of mTORC1 signaling and endolysosomal actin structures.
  6. Disruption of the Keap1-mTORC2 axis by cancer-derived Keap1/mLST8 mutations leads to oncogenic mTORC2-AKT activation.
  7. Oncogenic KRASG12D reprograms lipid metabolism by upregulating SLC25A1 to drive pancreatic tumorigenesis.
  1. Cancer Discov. 2023 Sep 15. OF1
    Proteostasis Network Modulation Promotes Resistance to KRAS Inhibitors.
      IRE1α-mediated proteostasis reprogramming is a key resistance mechanism to KRAS inhibitors.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-148
  2. Cancer Discov. 2023 Sep 15. OF1
    Differential Structural Dynamics Exist between Wild-type and Oncogenic K-Ras.
      Distinct dynamic signatures exist between wild-type, G12D mutant, and G12C mutant K-Ras-GTP and K-Ras-GDP.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-147
  3. Cell Biosci. 2023 Sep 09. 13(1): 164
    Phosphorylation at tyrosine 317 and 508 are crucial for PIK3CA/p110α to promote CRC tumorigenesis.
    Ting Wang, Longci Sun, Chengkun Chen, Yingchao Zhang, Baoyu He, Yanhua Zhang, Zhenghe Wang, Hanbing Xue, Yujun Hao.
      BACKGROUND: PI3K/AKT signaling pathway plays important role in tumorigenesis of human cancer. Protein phosphorylation is crucial for signaling transduction of this pathway. PIK3CA, encoding the catalytic subunit p110α of PI3K complex, is one of the most frequently mutated oncogenes in human cancers. However, phosphorylation sites of PIK3CA/p110α and their underlying mechanism in tumorigenesis are largely unknown.METHODS: Tyrosine phosphorylation sites of PIK3CA/p110α are identified with Mass-Spectrum. Crispr/CAS9 strategy is applied to generate Y317F and Y508F mutant knock-in cell clones. The growth and metastasis abilities of cells are evaluated in vitro and in vivo. Phospho-proteomics analysis and Western blots are used to demonstrate downstream signaling pathways of PIK3CA/p110α tyrosine phosphorylation. In vitro kinase assay is applied to identify the kinase of PIK3CA/p110α tyrosine phosphorylation.
    RESULTS: Tyrosine phosphorylation of PIK3CA/p110α is stimulated by growth factors such as EGF, HGF and PDGF. Two tyrosine residues, Y317 and Y508, are identified on PIK3CA/p110α. Either Y317 or Y508 phosphorylation is essential for tumorigenesis of CRC. Mutation at Y317 of p110α reduces the proliferation, migration, and invasion of cancer cells through Src-MLC2 pathway, while mutation at Y508 of p110α impairs AKT signaling. Moreover, Src interacts with and phosphorylates p110α.
    CONCLUSIONS: PIK3CA/p110α phosphorylation at Y317 and Y508 play important role in tumorigenesis of colorectal cancer through two independent pathways.
    Keywords:  Colorectal cancer; PI3K; Src; Tyrosine phosphorylation; p110α
    DOI:  https://doi.org/10.1186/s13578-023-01102-7
  4. Elife. 2023 Sep 12. pii: e74903. [Epub ahead of print]12
    Continuous sensing of nutrients and growth factors by the mTORC1-TFEB axis.
    Breanne Sparta, Nont Kosaisawe, Michael Pargett, Madhura Patankar, Nicholaus DeCuzzi, John G Albeck.
      mTORC1 senses nutrients and growth factors and phosphorylates downstream targets, including the transcription factor TFEB, to coordinate metabolic supply and demand. These functions position mTORC1 as a central controller of cellular homeostasis, but the behavior of this system in individual cells has not been well characterized. Here, we provide measurements necessary to refine quantitative models for mTORC1 as a metabolic controller. We developed a series of fluorescent protein-TFEB fusions and a multiplexed immunofluorescence approach to investigate how combinations of stimuli jointly regulate mTORC1 signaling at the single-cell level. Live imaging of individual MCF10A cells confirmed that mTORC1-TFEB signaling responds continuously to individual, sequential, or simultaneous treatment with amino acids and the growth factor insulin. Under physiologically relevant concentrations of amino acids, we observe correlated fluctuations in TFEB, AMPK, and AKT signaling that indicate continuous activity adjustments to nutrient availability. Using partial least squares regression modeling, we show that these continuous gradations are connected to protein synthesis rate via a distributed network of mTORC1 effectors, providing quantitative support for the qualitative model of mTORC1 as a homeostatic controller and clarifying its functional behavior within individual cells.
    Keywords:  cell biology; computational biology; human; systems biology
    DOI:  https://doi.org/10.7554/eLife.74903
  5. Sci Adv. 2023 Sep 15. 9(37): eadd9084
    Codependencies of mTORC1 signaling and endolysosomal actin structures.
    Amulya Priya, Sandra Antoine-Bally, Anne-Sophie Macé, Pedro Monteiro, Valentin Sabatet, David Remy, Florent Dingli, Damarys Loew, Constantinos Demetriades, Alexis M Gautreau, Philippe Chavrier.
      The mechanistic target of rapamycin complex 1 (mTORC1) is part of the amino acid sensing machinery that becomes activated on the endolysosomal surface in response to nutrient cues. Branched actin generated by WASH and Arp2/3 complexes defines endolysosomal microdomains. Here, we find mTORC1 components in close proximity to endolysosomal actin microdomains. We investigated for interactors of the mTORC1 lysosomal tether, RAGC, by proteomics and identified multiple actin filament capping proteins and their modulators. Perturbation of RAGC function affected the size of endolysosomal actin, consistent with a regulation of actin filament capping by RAGC. Reciprocally, the pharmacological inhibition of actin polymerization or alteration of endolysosomal actin obtained upon silencing of WASH or Arp2/3 complexes impaired mTORC1 activity. Mechanistically, we show that actin is required for proper association of RAGC and mTOR with endolysosomes. This study reveals an unprecedented interplay between actin and mTORC1 signaling on the endolysosomal system.
    DOI:  https://doi.org/10.1126/sciadv.add9084
  6. Redox Biol. 2023 Sep 05. pii: S2213-2317(23)00273-2. [Epub ahead of print]67 102872
    Disruption of the Keap1-mTORC2 axis by cancer-derived Keap1/mLST8 mutations leads to oncogenic mTORC2-AKT activation.
    Yingji Chen, Dongyue Jiao, Huiying He, Huiru Sun, Yajuan Liu, Qing Shi, Pingzhao Zhang, Yao Li, Ren Mo, Kun Gao, Chenji Wang.
      The mechanistic target of the rapamycin (mTOR) pathway, which participates in the regulation of cellular growth and metabolism, is aberrantly regulated in various cancer types. The mTOR complex 2 (mTORC2), which consists of the core components mTOR, Rictor, mSin1, and mLST8, primarily responds to growth signals. However, the coordination between mTORC2 assembly and activity remains poorly understood. Keap1, a major sensor of oxidative stress in cells, functions as a substrate adaptor for Cullin 3-RING E3 ubiquitin ligase (CRL3) to promote proteasomal degradation of NF-E2-related factor 2 (NRF2), which is a transcription factor that protects cells against oxidative and electrophilic stress. In the present study, we demonstrate that Keap1 binds to mLST8 via a conserved ETGE motif. The CRL3Keap1 ubiquitin ligase complex promotes non-degradative ubiquitination of mLST8, thus reducing mTORC2 complex integrity and mTORC2-AKT activation. However, this effect can be prevented by oxidative/electrophilic stresses and growth factor signaling-induced reactive oxygen species (ROS) burst. Cancer-derived Keap1 or mLST8 mutations disrupt the Keap1-mLST8 interaction and allow mLST8 to evade Keap1-mediated ubiquitination, thereby enhancing mTORC2-AKT activation and promoting cell malignancy and remodeling cell metabolism. Our findings provide new insights into the molecular mechanisms of Keap1/mLST8 mutation-driven tumorigenesis by promoting mTORC2-AKT activation, which is independent of the canonical NRF2 pathway.
    Keywords:  AKT; Keap1; Lung cancer; ROS; Ubiquitination; mTORC2
    DOI:  https://doi.org/10.1016/j.redox.2023.102872
  7. Cancer Res. 2023 Sep 11.
    Oncogenic KRASG12D reprograms lipid metabolism by upregulating SLC25A1 to drive pancreatic tumorigenesis.
    Ruowen Zhang, Xiaogang Peng, James Xianxing Du, Rebecca Boohaker, Igor L Estevao, Brian I Grajeda, Marc B Cox, Igor C Almeida, Weiqin Lu.
      Pancreatic cancer is a highly lethal disease with obesity as one of the risk factors. Oncogenic KRAS mutations are prevalent in pancreatic cancer and can rewire lipid metabolism by altering fatty acid (FA) uptake, FA oxidation (FAO), and lipogenesis. Identification of the underlying mechanisms could lead to improved therapeutic strategies for treating KRAS mutant pancreatic cancer. Here, we observed that KRASG12D upregulated the expression of SLC25A1, a citrate transporter that is a key metabolic switch to mediate FAO, fatty acid synthesis (FAS), glycolysis, and gluconeogenesis. In genetically engineered mouse models and human pancreatic cancer cells, KRASG12D induced SLC25A1 upregulation via GLI1, which directly stimulated SLC25A1 transcription by binding its promoter. The enhanced expression of SLC25A1 increased levels of cytosolic citrate, FAs, and key enzymes in lipid metabolism. In addition, a high-fat diet (HFD) further stimulated the KRASG12D-GLI1-SLC25A1 axis and the associated increase in citrate and FAs. Pharmacological inhibition of SLC25A1 and upstream GLI1 significantly suppressed pancreatic tumorigenesis in KrasG12D/+ mice on a HFD. These results reveal a KRASG12D-GLI1-SLC25A1 regulatory axis with SLC25A1 as an important node that regulates lipid metabolism during pancreatic tumorigenesis, thus indicating an intervention strategy for oncogenic KRAS-driven pancreatic cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-2679
This page is being maintained by Thomas Krichel. It was last updated on 2023‒09‒25 at 10:27.