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Chen J, Chitrakar R, Baugh LR. DAF-18/PTEN protects LIN-35/Rb from CLP-1/CAPN-mediated cleavage to promote starvation resistance. Life Sci Alliance 2025; 8:e202403147. [PMID: 40199585 PMCID: PMC11979363 DOI: 10.26508/lsa.202403147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 03/26/2025] [Accepted: 03/27/2025] [Indexed: 04/10/2025] Open
Abstract
Starvation resistance is a fundamental trait with profound influence on fitness and disease risk. DAF-18, the Caenorhabditis elegans ortholog of the tumor suppressor PTEN, promotes starvation resistance. PTEN is a dual phosphatase, and DAF-18 promotes starvation resistance as a lipid phosphatase by antagonizing insulin/IGF and PI3K signaling, activating the tumor suppressor DAF-16/FoxO. However, if or how DAF-18/PTEN protein-phosphatase activity promotes starvation resistance is unknown. Using genetic, genomic, bioinformatic, and biochemical approaches, we identified the C. elegans retinoblastoma/RB protein homolog, LIN-35/Rb, as a critical mediator of the effect of DAF-18/PTEN on starvation resistance. We show that DAF-18/PTEN protects LIN-35/Rb from cleavage by the μ-Calpain homolog CLP-1/CAPN, and that LIN-35/Rb together with the repressive DREAM complex promotes starvation resistance. We conclude that the tumor suppressors DAF-18/PTEN and LIN-35/Rb function in a linear pathway, with LIN-35/Rb and the rest of the DREAM complex functioning as a transcriptional effector of DAF-18/PTEN protein-phosphatase activity resulting in repression of germline gene expression. This work is significant for revealing a network of tumor suppressors that promote survival during cellular and developmental quiescence.
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Affiliation(s)
- Jingxian Chen
- Department of Biology, Duke University, Durham, NC, USA
| | | | - L Ryan Baugh
- Department of Biology, Duke University, Durham, NC, USA
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2
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Dexheimer TS, Davoudi Z, Coussens NP, Silvers T, Morris J, Takebe N, Said R, Moscow JA, Doroshow JH, Teicher BA. Combinatorial screen of targeted agents with the PI3K inhibitors inavolisib, alpelisib, duvelisib, and copanlisib in multi-cell type tumor spheroids. SLAS DISCOVERY : ADVANCING LIFE SCIENCES R & D 2025; 32:100222. [PMID: 39999911 PMCID: PMC12034487 DOI: 10.1016/j.slasd.2025.100222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 02/05/2025] [Accepted: 02/22/2025] [Indexed: 02/27/2025]
Abstract
Dysregulation of the phosphatidylinositol 3-kinase (PI3K) pathway is a key contributor to cancer, making PI3K inhibitors a promising approach for targeted therapy. The selectivity of available inhibitors varies across different PI3K isoforms. Alpelisib and inavolisib are selective for the α-isoform, while duvelisib targets the δ- and γ-isoforms, and copanlisib is a pan-PI3K inhibitor, active against all isoforms. This study investigated the activity of these four PI3K inhibitors in combination with other targeted agents using multi-cell type tumor spheroids composed of 60% malignant cells, 25% endothelial cells, and 15% mesenchymal stem cells. Twenty-nine tumor spheroid models were evaluated, including twenty-six patient-derived cancer cell lines from the NCI Patient-Derived Models Repository and three established cell lines from the NCI-60 human tumor cell line panel. Additive and/or synergistic effects were observed with alpelisib or inavolisib or copanlisib in combination with a RAS/MEK/ERK pathway inhibitor, either selumetinib (MEK), ravoxertinib (ERK 1/2), or tovorafenib (DAY101, RAF). Combinations of each of these three PI3K inhibitors with the KRAS mutation specific inhibitors MTRX1133 (KRAS G12D) or sotorasib (KRAS G12C) had selective activity in cell lines harboring the corresponding target. Lastly, combination effects were observed from vertical inhibition of the PI3K/AKT/mTOR pathway with a PI3K inhibitor in combination with either the mTORC1/2 inhibitor sapanisertib or an AKT inhibitor, ipatasertib or afuresertib.
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Affiliation(s)
- Thomas S Dexheimer
- Molecular Pharmacology Laboratory, Applied and Developmental Research Directorate, Frederick National Laboratory for Cancer Research, 1050 Boyles Street, Frederick, MD, 21702, USA.
| | - Zahra Davoudi
- Molecular Pharmacology Laboratory, Applied and Developmental Research Directorate, Frederick National Laboratory for Cancer Research, 1050 Boyles Street, Frederick, MD, 21702, USA
| | - Nathan P Coussens
- Molecular Pharmacology Laboratory, Applied and Developmental Research Directorate, Frederick National Laboratory for Cancer Research, 1050 Boyles Street, Frederick, MD, 21702, USA
| | - Thomas Silvers
- Molecular Pharmacology Laboratory, Applied and Developmental Research Directorate, Frederick National Laboratory for Cancer Research, 1050 Boyles Street, Frederick, MD, 21702, USA
| | - Joel Morris
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Naoko Takebe
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Rabih Said
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Jeffrey A Moscow
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - James H Doroshow
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Beverly A Teicher
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
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Chen J, Chitrakar R, Baugh LR. DAF-18/PTEN protects LIN-35/Rb from CLP-1/CAPN-mediated cleavage to promote starvation resistance. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.17.638677. [PMID: 40027768 PMCID: PMC11870551 DOI: 10.1101/2025.02.17.638677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Starvation resistance is a fundamental trait with profound influence on fitness and disease risk. DAF-18, the C. elegans ortholog of the tumor suppressor PTEN, promotes starvation resistance. PTEN is a dual phosphatase, and DAF-18 promotes starvation resistance as a lipid phosphatase by antagonizing insulin/IGF and PI3K signaling, activating the tumor suppressor DAF-16/FoxO. However, if or how DAF-18/PTEN protein-phosphatase activity promotes starvation resistance is unknown. Using genetic, genomic, bioinformatic, and biochemical approaches, we identified the C. elegans retinoblastoma/RB protein homolog, LIN-35/Rb, as a critical mediator of the effect of DAF-18/PTEN on starvation resistance. We show that DAF-18/PTEN protects LIN-35/Rb from cleavage by the μ-Calpain homolog CLP-1/CAPN, and that LIN-35/Rb together with the repressive DREAM complex promote starvation resistance. We conclude that the tumor suppressors DAF-18/PTEN and LIN-35/Rb function in a linear pathway, with LIN-35/Rb and the rest of the DREAM complex functioning as a transcriptional effector of DAF-18/PTEN protein-phosphatase activity resulting in repression of germline gene expression. This work is significant for revealing a network of tumor suppressors that promote survival during cellular and developmental quiescence.
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Garcia KC, Khan AA, Ghosh K, Sinha S, Scalora N, DeWane G, Fullenkamp C, Merritt N, Drebot Y, Yu S, Leidinger M, Henry MD, Breheny P, Chimenti MS, Tanas MR. PI3K regulates TAZ/YAP and mTORC1 axes that can be synergistically targeted. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.21.634138. [PMID: 39896636 PMCID: PMC11785051 DOI: 10.1101/2025.01.21.634138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Purpose Sarcomas are a heterogeneous group of cancers with few shared therapeutic targets. PI3K signaling is activated in various subsets of sarcomas, representing a shared oncogenic signaling pathway. Oncogenic PI3K signaling has been challenging to target therapeutically. An integrated view of PI3K and Hippo pathway signaling is examined to determine if this could be leveraged therapeutically. Experimental design A tissue microarray containing sarcomas of various histological types was evaluated for PTEN loss and correlated with levels of activated TAZ and YAP. PI3K and Hippo pathways were dissected in sarcoma cell lines. The role of TAZ and YAP were evaluated in a PI3K-driven mouse model. The efficacy of mTORC1 inhibition and TEAD inhibition were evaluated in sarcoma cell lines and in vivo . Results PI3K signaling is frequently activated in sarcomas due to PTEN loss (in 30-60%), representing a common therapeutic target. TAZ and YAP are transcriptional co-activators regulated by PI3K and drive a transcriptome necessary for tumor growth in a PI3K-driven sarcoma mouse model. Combination therapy using IK-930 (TEAD inhibitor) and everolimus (mTORC1 inhibitor) synergistically diminished proliferation and anchorage independent growth of PI3K-activated sarcoma cell lines at low, physiologically achievable doses. Furthermore, this combination therapy showed a synergistic effect in vivo , reducing tumor proliferation and size. Conclusions TAZ and YAP are transcriptional co-activators downstream of PI3K signaling, a pathway that has lacked a well-defined oncogenic transcription factor. This PI3K-TAZ/YAP axis exists in parallel to the known PI3K-Akt-mTORC1 axis allowing for synergistic combination therapy targeting the TAZ/YAP-TEAD interaction and mTORC1 in sarcomas.
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Jun HJ, Paulo JA, Appleman VA, Yaron-Barir TM, Johnson JL, Yeo AT, Rogers VA, Kuang S, Varma H, Gygi SP, Trotman LC, Charest A. Pleiotropic tumor suppressive functions of PTEN missense mutations during gliomagenesis. iScience 2024; 27:111278. [PMID: 39660053 PMCID: PMC11629276 DOI: 10.1016/j.isci.2024.111278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 10/24/2024] [Accepted: 10/25/2024] [Indexed: 12/12/2024] Open
Abstract
PTEN plays a crucial role in preventing the development of glioblastoma (GBM), a severe and untreatable brain cancer. In GBM, most PTEN deficiencies are missense mutations that have not been thoroughly examined. Here, we leveraged genetically modified mice and isogenic astrocyte cell cultures to investigate the role of clinically relevant mutations (G36E, L42R, C105F, and R173H) in the development of EGFR-driven GBM. We report that the loss of tumor suppression from these mutants is unrelated to their lipid phosphatase activity and rather relate to elevated localization at the cell membrane. Moreover, expression of these PTEN mutations heightened EGFR activity by sequestering EGFR within endomembranes longer and affected its signaling behavior. Through comprehensive studies on global protein phosphorylation and kinase library analyses in cells with the G36E and L42R PTEN mutations, we identified distinct cancer-promoting pathways activated by EGFR, offering targets for treating GBM with these PTEN alterations.
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Affiliation(s)
- Hyun Jung Jun
- Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
| | - Joao A. Paulo
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Victoria A. Appleman
- Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
| | - Tomer M. Yaron-Barir
- Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
| | - Jared L. Johnson
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Alan T. Yeo
- Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
| | - Vaughn A. Rogers
- Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
| | - Shan Kuang
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Hemant Varma
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Steven P. Gygi
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Lloyd C. Trotman
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Al Charest
- Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
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Endicott SJ. Chaperone-mediated autophagy as a modulator of aging and longevity. FRONTIERS IN AGING 2024; 5:1509400. [PMID: 39687864 PMCID: PMC11647017 DOI: 10.3389/fragi.2024.1509400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 11/18/2024] [Indexed: 12/18/2024]
Abstract
Chaperone-mediated autophagy (CMA) is the lysosomal degradation of individually selected proteins, independent of vesicle fusion. CMA is a central part of the proteostasis network in vertebrate cells. However, CMA is also a negative regulator of anabolism, and it degrades enzymes required for glycolysis, de novo lipogenesis, and translation at the cytoplasmic ribosome. Recently, CMA has gained attention as a possible modulator of rodent aging. Two mechanistic models have been proposed to explain the relationship between CMA and aging in mice. Both of these models are backed by experimental data, and they are not mutually exclusionary. Model 1, the "Longevity Model," states that lifespan-extending interventions that decrease signaling through the INS/IGF1 signaling axis also increase CMA, which degrades (and thereby reduces the abundance of) several proteins that negatively regulate vertebrate lifespan, such as MYC, NLRP3, ACLY, and ACSS2. Therefore, enhanced CMA, in early and midlife, is hypothesized to slow the aging process. Model 2, the "Aging Model," states that changes in lysosomal membrane dynamics with age lead to age-related losses in the essential CMA component LAMP2A, which in turn reduces CMA, contributes to age-related proteostasis collapse, and leads to overaccumulation of proteins that contribute to age-related diseases, such as Alzheimer's disease, Parkinson's disease, cancer, atherosclerosis, and sterile inflammation. The objective of this review paper is to comprehensively describe the data in support of both of these explanatory models, and to discuss the strengths and limitations of each.
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Affiliation(s)
- S. Joseph Endicott
- Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
- Autophagy, Inflammation, and Metabolism Center of Biomedical Research Excellence, (AIM CoBRE), University of New Mexico Health Sciences Center, Albuquerque, NM, United States
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Wei R, Hitomi M, Sadler T, Yehia L, Calvetti D, Scott J, Eng C. Quantitative evaluation of DNA damage repair dynamics to elucidate predictors of autism vs. cancer in individuals with germline PTEN variants. PLoS Comput Biol 2024; 20:e1012449. [PMID: 39356721 PMCID: PMC11472915 DOI: 10.1371/journal.pcbi.1012449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 10/14/2024] [Accepted: 08/31/2024] [Indexed: 10/04/2024] Open
Abstract
Persons with germline variants in the tumor suppressor gene phosphatase and tensin homolog, PTEN, are molecularly diagnosed with PTEN hamartoma tumor syndrome (PHTS). PHTS confers high risks of specific malignancies, and up to 23% of the patients are diagnosed with autism spectrum disorder (ASD) and/or developmental delay (DD). The accurate prediction of these two seemingly disparate phenotypes (cancer vs. ASD/DD) for PHTS at the individual level remains elusive despite the available statistical prevalence of specific phenotypes of the syndrome at the population level. The pleiotropy of the syndrome may, in part, be due to the alterations of the key multi-functions of PTEN. Maintenance of genome integrity is one of the key biological functions of PTEN, but no integrative studies have been conducted to quantify the DNA damage response (DDR) in individuals with PHTS and to relate to phenotypes and genotypes. In this study, we used 43 PHTS patient-derived lymphoblastoid cell lines (LCLs) to investigate the associations between DDR and PTEN genotypes and/or clinical phenotypes ASD/DD vs. cancer. The dynamics of DDR of γ-irradiated LCLs were analyzed using the exponential decay mathematical model to fit temporal changes in γH2AX levels which report the degree of DNA damage. We found that PTEN nonsense variants are associated with less efficient DNA damage repair ability resulting in higher DNA damage levels at 24 hours after irradiation compared to PTEN missense variants. Regarding PHTS phenotypes, LCLs from PHTS individuals with ASD/DD showed faster DNA damage repairing rate than those from patients without ASD/DD or cancer. We also applied the reaction-diffusion partial differential equation (PDE) mathematical model, a cell growth model with a DNA damage term, to accurately describe the DDR process in the LCLs. For each LCL, we can derive parameters of the PDE. Then we averaged the numerical results by PHTS phenotypes. By performing simple subtraction of two subgroup average results, we found that PHTS-ASD/DD is associated with higher live cell density at lower DNA damage level but lower cell density level at higher DNA damage level compared to LCLs from individuals with PHTS-cancer and PHTS-neither.
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Affiliation(s)
- Ruipeng Wei
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
- Department of Nutrition and Systems Biology and Bioinformatics Program, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
| | - Masahiro Hitomi
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
- Translational Hematology & Oncology Research, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Tammy Sadler
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Lamis Yehia
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Daniela Calvetti
- Department of Mathematics, Applied Mathematics, and Statistics, Case Western Reserve University College of Arts and Sciences, Cleveland, Ohio, United States of America
| | - Jacob Scott
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
- Translational Hematology & Oncology Research, Cleveland Clinic, Cleveland, Ohio, United States of America
- Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio, United States of America
- Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Charis Eng
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
- Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
- Center for Personalized Genetic Healthcare, Medical Specialties Institute, Cleveland Clinic, United States of America
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
- Germline High Risk Cancer Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
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Tian Y, Liu YF, Wang YY, Li YZ, Ding WY, Zhang C. Molecular mechanisms of PTEN in atherosclerosis: A comprehensive review. Eur J Pharmacol 2024; 979:176857. [PMID: 39094923 DOI: 10.1016/j.ejphar.2024.176857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 07/17/2024] [Accepted: 07/24/2024] [Indexed: 08/04/2024]
Abstract
Atherosclerosis is a chronic inflammatory disease of the arterial wall caused by an imbalance of lipid metabolism and a maladaptive inflammatory response. A variety of harmful cellular changes associated with atherosclerosis include endothelial dysfunction, the migration of circulating inflammatory cells to the arterial wall, the production of proinflammatory cytokines, lipid buildup in the intima, local inflammatory responses in blood vessels, atherosclerosis-associated apoptosis, and autophagy. PTEN inhibits the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT)/mammalian target of rapamycin (mTOR) pathway through its lipid phosphatase activity. Previous studies have shown that PTEN is closely related to atherosclerosis. This article reviews the role of PTEN in atherosclerosis from the perspectives of autophagy, apoptosis, inflammation, proliferation, and angiogenesis.
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Affiliation(s)
- Yuan Tian
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan province, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People's Republic of China
| | - Yi-Fan Liu
- Research Laboratory of Translational Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People's Republic of China
| | - Yan-Yue Wang
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan province, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People's Republic of China
| | - Yong-Zhen Li
- Department of Pathology, The First People's Hospital of Zigong, Zigong, China, 643099, People's Republic of China
| | - Wen-Yan Ding
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan province, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People's Republic of China
| | - Chi Zhang
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan province, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People's Republic of China.
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Che L, Stevenson CK, Plas DR, Wang J, Du C. BRUCE liver-deficiency potentiates MASLD/MASH in PTEN liver-deficient background by impairment of mitochondrial metabolism in hepatocytes and activation of STAT3 signaling in hepatic stellate cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.13.611500. [PMID: 39314445 PMCID: PMC11419131 DOI: 10.1101/2024.09.13.611500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common liver disease, affecting up to 25% of people worldwide, featuring excessive fat accumulation in hepatocytes. Its advanced form, metabolic dysfunction-associated steatohepatitis (MASH), is a serious disease with hepatic inflammation and fibrosis, increasing the need for liver transplants. However, the pathogenic mechanism of MASLD and MASH is not fully understood. We reported that BRUCE ( BIRC6) is a liver cancer suppressor and is downregulated in MASLD/MASH patient liver specimens, though the functional role of BRUCE in MASLD/MASH remains to be elucidated. To this end, we generated liver-specific double KO (DKO) mice of BRUCE and PTEN, a major tumor suppressor and MASLD/MASH suppressor. By comparing liver histopathology among 2-3-month-old mice, there were no signs of MASLD or MASH in BRUCE liver-KO mice and only onset of steatosis in PTEN liver-KO mice. Interestingly, DKO mice had developed robust hepatic steatosis with inflammation and fibrosis. Further analysis of mitochondrial function with primary hepatocytes found moderate reduction of mitochondrial respiration, ATP production and fatty acid oxidation in BRUCE KO and the greatest reduction in DKO hepatocytes. Moreover, aberrant activation of pro-fibrotic STAT3 signaling was found in hepatic stellate cells (HSCs) in DKO mice which was prevented by administered STAT3-specific inhibitor (TTI-101). Collectively, the data demonstrates by maintaining mitochondrial metabolism BRUCE works in concert with PTEN to suppress the pro-fibrogenic STAT3 activation in HSCs and consequentially prevent MASLD/MASH. The findings highlight BRUCE being a new co-suppressor of MASLD/MASH.
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Geng L, Bai Z, Wen X, Liu H, Xie H, Wang Y, Wu W, Zeng Z, Zheng K. PTEN-Long inhibits the biological behaviors of glioma cells. Am J Transl Res 2024; 16:2840-2851. [PMID: 39114725 PMCID: PMC11301513 DOI: 10.62347/qhca5842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 06/11/2024] [Indexed: 08/10/2024]
Abstract
OBJECTIVES PTEN-Long is a translational variant of phosphatase and tensin homolog (PTEN). This study aimed to assess the effect of PTEN-Long on the biological characteristics of glioma cells and related mechanisms. METHODS A vector stably expressing PTEN-Long was established and transfected into cells, serving as the overexpression group, while a set of empty vectors served as the negative control group. Real-time reverse transcription-polymerase chain reaction (RT-PCR) and western blot were used to detect the expression of PTEN-Long and phosphatidylinositol 3-kinase, Protein kinase B, andnuclear factor-κB (PI3K-AKT-NF-κB). Cell proliferation was assessed with the Cell Counting Kit 8 (CCK8) assay, migration through the scratch test, and invasion by the transwell chamber assay. Cell cycle analysis was performed using flow cytometry. The volume and weight of subcutaneous tumors in nude mice were also evaluated. RESULTS PTEN-Long expression led to downregulation of p-Akt, NF-κB p65, p-NF-κB p65, and Bcl-xl, and up-regulation of IκBα. In addition, it inhibited glioma cell proliferation, induced cell cycle arrest in the G0/G1 phase, and reduced cell migration and invasion. Moreover, PTEN-Long inhibited the growth of subcutaneous glioma in nude mice. CONCLUSIONS PTEN-Long inhibits the proliferation, migration, and invasion and induces apoptosis in glioma cells by inhibiting PI3K-AKT-NF-κb signaling, implying that PTEN-Long may be a new target for glioma treatment.
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Affiliation(s)
- Lianting Geng
- Department of Neurosurgery, Affiliated Hospital of Hebei UniversityBaoding 071000, Hebei, China
| | - Zetong Bai
- Department of Neurosurgery, Affiliated Hospital of Hebei UniversityBaoding 071000, Hebei, China
| | - Xichao Wen
- Department of Neurosurgery, Affiliated Hospital of Hebei UniversityBaoding 071000, Hebei, China
| | - Haipeng Liu
- Department of Neurosurgery, Affiliated Hospital of Hebei UniversityBaoding 071000, Hebei, China
| | - Haipeng Xie
- Department of Neurosurgery, Affiliated Hospital of Hebei UniversityBaoding 071000, Hebei, China
| | - Yan Wang
- Department of Neurosurgery, Affiliated Hospital of Hebei UniversityBaoding 071000, Hebei, China
| | - Wensong Wu
- Department of Neurosurgery, Affiliated Hospital of Hebei UniversityBaoding 071000, Hebei, China
| | - Zhaomu Zeng
- Department of Neurosurgery, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical CollegeNanchang 330000, Jiangxi, China
| | - Kebin Zheng
- Department of Neurosurgery, Affiliated Hospital of Hebei UniversityBaoding 071000, Hebei, China
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11
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Malin J, Rosa-Birriel C, Hatini V. Pten, PI3K, and PtdIns(3,4,5)P 3 dynamics control pulsatile actin branching in Drosophila retina morphogenesis. Dev Cell 2024; 59:1593-1608.e6. [PMID: 38640926 DOI: 10.1016/j.devcel.2024.03.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 11/28/2023] [Accepted: 03/25/2024] [Indexed: 04/21/2024]
Abstract
Epithelial remodeling of the Drosophila retina depends on the pulsatile contraction and expansion of apical contacts between the cells that form its hexagonal lattice. Phosphoinositide PI(3,4,5)P3 (PIP3) accumulates around tricellular adherens junctions (tAJs) during contact expansion and dissipates during contraction, but with unknown function. Here, we found that manipulations of Pten or PI3-kinase (PI3K) that either decreased or increased PIP3 resulted in shortened contacts and a disordered lattice, indicating a requirement for PIP3 dynamics and turnover. These phenotypes are caused by a loss of branched actin, resulting from impaired activity of the Rac1 Rho GTPase and the WAVE regulatory complex (WRC). We additionally found that during contact expansion, PI3K moves into tAJs to promote the cyclical increase of PIP3 in a spatially and temporally precise manner. Thus, dynamic control of PIP3 by Pten and PI3K governs the protrusive phase of junctional remodeling, which is essential for planar epithelial morphogenesis.
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Affiliation(s)
- Jacob Malin
- Tufts University School of Medicine, Department of Developmental, Molecular & Chemical Biology, Program in Genetics, Molecular and Cellular Biology, and Program in Pharmacology and Experimental Therapeutics, 150 Harrison Avenue, Boston, MA 02111, USA
| | - Christian Rosa-Birriel
- Tufts University School of Medicine, Department of Developmental, Molecular & Chemical Biology, Program in Genetics, Molecular and Cellular Biology, and Program in Pharmacology and Experimental Therapeutics, 150 Harrison Avenue, Boston, MA 02111, USA
| | - Victor Hatini
- Tufts University School of Medicine, Department of Developmental, Molecular & Chemical Biology, Program in Genetics, Molecular and Cellular Biology, and Program in Pharmacology and Experimental Therapeutics, 150 Harrison Avenue, Boston, MA 02111, USA.
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12
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Wu H, Wang J, Bu Y, Li J, Li Y, Jing Q, Wang X, Yan C, Liu D, Han Y. Pentamethylquercetin attenuates angiotensin II-induced abdominal aortic aneurysm formation by blocking nuclear translocation of C/EBPβ at Lys253. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167224. [PMID: 38723872 DOI: 10.1016/j.bbadis.2024.167224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 04/30/2024] [Accepted: 05/03/2024] [Indexed: 05/12/2024]
Abstract
BACKGROUND Pentamethylquercetin (PMQ) is a natural polymethyl flavonoid that possesses anti-apoptotic and other biological properties. Abdominal aortic aneurysm (AAA), a fatal vascular disease with a high risk of rupture, is associated with phenotypic switching and apoptosis of medial vascular smooth muscle cells (VSMCs). This study aimed to investigate the protective effects of PMQ on the development of AAA and the underlying mechanism. METHODS ApoE-/- mice were continuously infused with angiotensin II (Ang II) for 4 weeks to develop the AAA model. Intragastric administration of PMQ was initiated 5 days before Ang II infusion and continued for 4 weeks. In vitro, VSMCs were cultured and pretreated with PMQ, stimulated with Ang II. Real-time PCR, western blotting, and immunofluorescence staining were used to examine the roles and mechanisms of PMQ on the phenotypic switching and apoptosis of VSMCs. RESULTS PMQ dose-dependently reduced the incidence of Ang II-induced AAA, aneurysm diameter enlargement, elastin degradation, VSMCs phenotypic switching and apoptosis. Furthermore, PMQ also inhibited phenotypic switching and apoptosis in Ang II-stimulated VSMCs. PMQ exerted protective effects by regulating the C/EBPβ/PTEN/AKT/GSK-3β axis. AAV-mediated overexpression of PTEN reduced the therapeutic effects of PMQ in the AAA model mice, suggesting that the effects of PMQ on Ang II-mediated AAA formation were related to the PTEN/AKT/GSK-3β axis. PMQ inhibited VSMCs phenotypic switching and apoptosis by bounding to C/EBPβ at Lys253 with hydrogen bond to regulate C/EBPβ nuclear translocation and PTEN/AKT/GSK-3β axis, thereby inhibiting Ang II-induced AAA formation. CONCLUSIONS Pentamethylquercetin inhibits angiotensin II-induced abdominal aortic aneurysm formation by bounding to C/EBPβ at Lys253. Therefore, PMQ prevents the formation of AAA and reduces the incidence of AAA.
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MESH Headings
- Animals
- Aortic Aneurysm, Abdominal/metabolism
- Aortic Aneurysm, Abdominal/pathology
- Aortic Aneurysm, Abdominal/prevention & control
- Aortic Aneurysm, Abdominal/chemically induced
- Aortic Aneurysm, Abdominal/drug therapy
- Angiotensin II/pharmacology
- Mice
- Quercetin/analogs & derivatives
- Quercetin/pharmacology
- Apoptosis/drug effects
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/pathology
- Male
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/pathology
- Disease Models, Animal
- PTEN Phosphohydrolase/metabolism
- PTEN Phosphohydrolase/genetics
- Proto-Oncogene Proteins c-akt/metabolism
- Mice, Inbred C57BL
- Glycogen Synthase Kinase 3 beta/metabolism
- Signal Transduction/drug effects
- Cells, Cultured
- Cell Nucleus/metabolism
- Cell Nucleus/drug effects
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Affiliation(s)
- Hanlin Wu
- Dalian Medical University, Dalian, Liaoning Province 116044, China; State Key Laboratory of Frigid Zone Cardiovascular Diseases, Department of Cardiology and Cardiovascular Research Institute of PLA, General Hospital of Northern Theater Command, Shenyang, Liaoning Province 110016, China
| | - Jing Wang
- Dalian Medical University, Dalian, Liaoning Province 116044, China; State Key Laboratory of Frigid Zone Cardiovascular Diseases, Department of Cardiology and Cardiovascular Research Institute of PLA, General Hospital of Northern Theater Command, Shenyang, Liaoning Province 110016, China
| | - Yuxin Bu
- State Key Laboratory of Frigid Zone Cardiovascular Diseases, Department of Cardiology and Cardiovascular Research Institute of PLA, General Hospital of Northern Theater Command, Shenyang, Liaoning Province 110016, China
| | - Jia Li
- State Key Laboratory of Frigid Zone Cardiovascular Diseases, Department of Cardiology and Cardiovascular Research Institute of PLA, General Hospital of Northern Theater Command, Shenyang, Liaoning Province 110016, China
| | - Yiming Li
- State Key Laboratory of Frigid Zone Cardiovascular Diseases, Department of Cardiology and Cardiovascular Research Institute of PLA, General Hospital of Northern Theater Command, Shenyang, Liaoning Province 110016, China
| | - Quanmin Jing
- State Key Laboratory of Frigid Zone Cardiovascular Diseases, Department of Cardiology and Cardiovascular Research Institute of PLA, General Hospital of Northern Theater Command, Shenyang, Liaoning Province 110016, China
| | - Xiaozeng Wang
- State Key Laboratory of Frigid Zone Cardiovascular Diseases, Department of Cardiology and Cardiovascular Research Institute of PLA, General Hospital of Northern Theater Command, Shenyang, Liaoning Province 110016, China
| | - Chenghui Yan
- State Key Laboratory of Frigid Zone Cardiovascular Diseases, Department of Cardiology and Cardiovascular Research Institute of PLA, General Hospital of Northern Theater Command, Shenyang, Liaoning Province 110016, China
| | - Dan Liu
- State Key Laboratory of Frigid Zone Cardiovascular Diseases, Department of Cardiology and Cardiovascular Research Institute of PLA, General Hospital of Northern Theater Command, Shenyang, Liaoning Province 110016, China.
| | - Yaling Han
- State Key Laboratory of Frigid Zone Cardiovascular Diseases, Department of Cardiology and Cardiovascular Research Institute of PLA, General Hospital of Northern Theater Command, Shenyang, Liaoning Province 110016, China.
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13
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Kashani Khatib Z, Maleki A, Pourfatollah AA, Hamidieh AA, Ferdowsi S. Antileukemia Activity of Human Natural Killer Cell-Derived Nanomagic Bullets against Acute Myeloid Leukemia (AML). Int J Hematol Oncol Stem Cell Res 2024; 18:123-139. [PMID: 38868808 PMCID: PMC11166499 DOI: 10.18502/ijhoscr.v18i2.15368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 04/26/2022] [Indexed: 06/14/2024] Open
Abstract
Background: Cancer is among the serious health problems of the medical world, for treatment of which severe treatments are used. However, the prognosis of cancer patients is still poor. The application of NK cell-derived exosomes (NK-Exo) is a new method for cancer immunotherapy. These nanoparticles with a size range of 30-120 nm are a small model of mother cells. In this study, the anti-tumor activity of NK-Exo and LAK-Exo (activated NK cell-derived exosome) against acute myeloid leukemia (AML) is investigated in vitro. Materials and Methods: The MACS method was performed for the separation of NK cells from the buffy coats of healthy donors, and an EXOCIBE kit was used for the isolation of NK-Exo. After treating the KG-1 cell line with different doses of NK-Exo, MTT assay, and annexin V-PE were done to evaluate cell proliferation and apoptosis, respectively, and for confirmation of involved proteins, Real-Time PCR and western blotting were performed. Results: Anti-tumor activity of NK-Exo and LAK-Exo was dose- and time-dependent. Their highest activities were observed following 48 hours of incubation with 50 µg/ml exosome (p<0.0001). However, this cytotoxic activity was also seen over a short period of time with low concentrations of NK-Exo (p<0.05) and LAK-Exo (p<0.001).The cytotoxic effect of LAK-Exo on target cells was significantly higher than NK-EXO. The induction of apoptosis by different pathways was time-point dependent. Total apoptosis was 34.56% and 51.6% after 48 hours of tumor cell coculture with 50µg/ml NK-Exo and LAK-Exo, respectively. Significant expression of CASPASE3, P38, and CYTOCHROME C genes was observed in the cells treated with 50 µg/ml NK-Exo and LAK-Exo. Conclusion: Our study confirmed the antileukemia activity of NK-Exo against AML tumor cells in vitro. Therefore, NK-Exo can be considered as a promising and effective treatment for leukemia therapy.
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Affiliation(s)
- Zahra Kashani Khatib
- Department of Hematology, Allied Medical School, Tehran University of Medical Sciences, Tehran, Iran
| | - Asma Maleki
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ali Akbar Pourfatollah
- Department of Immunology, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
| | - Amir Ali Hamidieh
- Department of Pediatric Stem Cell Transplantation, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Pediatric Cell Therapy Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Shirin Ferdowsi
- High Institute for Research and Education in Transfusion Medicine, Iranian Blood Transfusion Organization, Tehran, Iran
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14
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Gambini D, Ferrero S, Bulfamante G, Pisani L, Corbo M, Kuhn E. Cerebellar phenotypes in germline PTEN mutation carriers. Neuropathol Appl Neurobiol 2024; 50:e12970. [PMID: 38504418 DOI: 10.1111/nan.12970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 02/21/2024] [Accepted: 02/25/2024] [Indexed: 03/21/2024]
Abstract
PTEN hamartoma tumour syndrome (PHTS) comprises different hereditary conditions caused by germline PTEN mutations, predisposing to the development of multiple hamartomas in many body tissues and also increasing the risk of some types of cancer. Cerebellar involvement in PHTS patients has been long known due to the development of a pathognomonic cerebellar hamartoma (known as dysplastic gangliocytoma of the cerebellum or Lhermitte-Duclos disease). Recently, a crucial role of the cerebellum has been highlighted in the pathogenesis of autism spectrum disorders, now recognised as a phenotype expressed in a variable percentage of PHTS children. In addition, rare PTEN variants are indeed identified in medulloblastoma as well, even if they are less frequent than other germline gene mutations. The importance of PTEN and its downstream signalling enzymatic pathways, PI3K/AKT/mTOR, has been studied at different levels in both human clinical settings and animal models, not only leading to a better understanding of the pathogenesis of different disorders but, most importantly, to identify potential targets for specific therapies. In particular, PTEN integrity makes an important contribution to the normal development of tissue architecture in the nervous system, including the cerebellum. Thus, in patients with PTEN germline mutations, the cerebellum is an affected organ that is increasingly recognised in different disorders, whereas, in animal models, cerebellar Pten loss causes a variety of functional and histological alterations. In this review, we summarise the range of cerebellar involvement observed in PHTS and its relationships with germline PTEN mutations, along with the phenotypes expressed by murine models with PTEN deficiency in cerebellar tissue.
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Affiliation(s)
- Donatella Gambini
- Department of Neurorehabilitation Sciences, Casa di Cura Igea, Milan, Italy
| | - Stefano Ferrero
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy
- Pathology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Gaetano Bulfamante
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy
- Human Pathology and Molecular Pathology Unit, TOMA Advanced Biomedical Assays, Busto Arsizio, Italy
| | - Luigi Pisani
- Department of Neurorehabilitation Sciences, Casa di Cura Igea, Milan, Italy
| | - Massimo Corbo
- Department of Neurorehabilitation Sciences, Casa di Cura Igea, Milan, Italy
| | - Elisabetta Kuhn
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy
- Pathology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
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15
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Phan AT, Zhu Y. PTEN Mediates the Silencing of Unintegrated HIV-1 DNA. Viruses 2024; 16:291. [PMID: 38400066 PMCID: PMC10892664 DOI: 10.3390/v16020291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 01/31/2024] [Accepted: 02/12/2024] [Indexed: 02/25/2024] Open
Abstract
The integration of viral DNA into a host genome is an important step in HIV-1 replication. However, due to the high failure rate of integration, the majority of viral DNA exists in an unintegrated state during HIV-1 infection. In contrast to the robust expression from integrated viral DNA, unintegrated HIV-1 DNA is very poorly transcribed in infected cells, but the molecular machinery responsible for the silencing of unintegrated HIV-1 DNA remains poorly characterized. In this study, we sought to characterize new host factors for the inhibition of expression from unintegrated HIV-1 DNA. A genome-wide CRISPR-Cas9 knockout screening revealed the essential role of phosphatase and tensin homolog (PTEN) in the silencing of unintegrated HIV-1 DNA. PTEN's phosphatase activity negatively regulates the PI3K-Akt pathway to inhibit the transcription from unintegrated HIV-1 DNA. The knockout (KO) of PTEN or inhibition of PTEN's phosphatase activity by point mutagenesis activates Akt by phosphorylation and enhances the transcription from unintegrated HIV-1 DNA. Inhibition of the PI3K-Akt pathway by Akt inhibitor in PTEN-KO cells restores the silencing of unintegrated HIV-1 DNA. Transcriptional factors (NF-κB, Sp1, and AP-1) are important for the activation of unintegrated HIV-1 DNA in PTEN-KO cells. Finally, the knockout of PTEN increases the levels of active epigenetic marks (H3ac and H3K4me3) and the recruitment of PolII on unintegrated HIV-1 DNA chromatin. Our experiments reveal that PTEN targets transcription factors (NF-κB, Sp1, and AP-1) by negatively regulating the PI3K-Akt pathway to promote the silencing of unintegrated HIV-1 DNA.
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Affiliation(s)
| | - Yiping Zhu
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA;
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16
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Skalka GL, Tsakovska M, Murphy DJ. Kinase signalling adaptation supports dysfunctional mitochondria in disease. Front Mol Biosci 2024; 11:1354682. [PMID: 38434478 PMCID: PMC10906720 DOI: 10.3389/fmolb.2024.1354682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 01/15/2024] [Indexed: 03/05/2024] Open
Abstract
Mitochondria form a critical control nexus which are essential for maintaining correct tissue homeostasis. An increasing number of studies have identified dysregulation of mitochondria as a driver in cancer. However, which pathways support and promote this adapted mitochondrial function? A key hallmark of cancer is perturbation of kinase signalling pathways. These pathways include mitogen activated protein kinases (MAPK), lipid secondary messenger networks, cyclic-AMP-activated (cAMP)/AMP-activated kinases (AMPK), and Ca2+/calmodulin-dependent protein kinase (CaMK) networks. These signalling pathways have multiple substrates which support initiation and persistence of cancer. Many of these are involved in the regulation of mitochondrial morphology, mitochondrial apoptosis, mitochondrial calcium homeostasis, mitochondrial associated membranes (MAMs), and retrograde ROS signalling. This review will aim to both explore how kinase signalling integrates with these critical mitochondrial pathways and highlight how these systems can be usurped to support the development of disease. In addition, we will identify areas which require further investigation to fully understand the complexities of these regulatory interactions. Overall, this review will emphasize how studying the interaction between kinase signalling and mitochondria improves our understanding of mitochondrial homeostasis and can yield novel therapeutic targets to treat disease.
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Affiliation(s)
- George L. Skalka
- School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Mina Tsakovska
- School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Daniel J. Murphy
- School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
- CRUK Scotland Institute, Glasgow, United Kingdom
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17
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De D, Ghosh G, Karmakar P. Sumoylation and phosphorylation of PTEN boosts and curtails autophagy respectively by influencing cell membrane localisation. Exp Cell Res 2024; 434:113872. [PMID: 38072303 DOI: 10.1016/j.yexcr.2023.113872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 11/30/2023] [Accepted: 12/03/2023] [Indexed: 12/17/2023]
Abstract
Autophagy is involved in the entirety of cellular survival, homeostasis and death which becomes more self-evident when its dysregulation is implicated in several pathological conditions. PTEN positively regulates autophagy and like other proteins undergo post-translational modifications. It is crucial to investigate the relationship between PTEN and autophagy as it is generally observed to be negligible in PTEN deficient cancer cells. Here, we have shown that such modifications of PTEN namely sumoylation and phosphorylation upregulates and downregulates autophagy respectively. Transfection of plasmid containing full length PTEN in PTEN-negative prostate cancer cell line PC3, induced autophagy on further starvation. When a sumoylation-deficient mutant of PTEN was transfected and cells were put under similar starvation, a decline in autophagy was observed. On the other hand, cells transfected with phosphorylation-deficient mutant of PTEN showed elevated expression of autophagy. Contrarily, transfection with phosphorylation-mimicking mutant caused reduced expression of autophagy. On further analysis, it was detected that PTEN's association with the plasma membrane was under positive and negative influence from its sumoylation and phosphorylation respectively. This association is integral as it is the foremost site for PTEN to oppose PI3K/AKT pathway and consequently upregulate autophagy. Thus, this study indicates that sumoylation and phosphorylation of PTEN can control autophagy via its cell membrane association.
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Affiliation(s)
- Debojyoti De
- Department of Life Science & Biotechnology, Jadavpur University, 188, Raja Subodh Chandra Mallick Road, Jadavpur, Kolkata, 700032, West Bengal, India.
| | - Ginia Ghosh
- Department of Life Science & Biotechnology, Jadavpur University, 188, Raja Subodh Chandra Mallick Road, Jadavpur, Kolkata, 700032, West Bengal, India.
| | - Parimal Karmakar
- Department of Life Science & Biotechnology, Jadavpur University, 188, Raja Subodh Chandra Mallick Road, Jadavpur, Kolkata, 700032, West Bengal, India.
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18
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Mu C, Gao M, Xu W, Sun X, Chen T, Xu H, Qiu H. Mechanisms of microRNA-132 in central neurodegenerative diseases: A comprehensive review. Biomed Pharmacother 2024; 170:116029. [PMID: 38128185 DOI: 10.1016/j.biopha.2023.116029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 12/12/2023] [Accepted: 12/14/2023] [Indexed: 12/23/2023] Open
Abstract
MicroRNA-132 (miR-132) is a highly conserved molecule that plays a crucial regulatory role in central nervous system (CNS) disorders. The expression levels of miR-132 exhibit variability in various neurological disorders and have been closely linked to disease onset and progression. The expression level of miR-132 in the CNS is regulated by a diverse range of stimuli and signaling pathways, including neuronal migration and integration, dendritic outgrowth, and complexity, synaptogenesis, synaptic plasticity, as well as inflammation and apoptosis activation. The aberrant expression of miR-132 in various central neurodegenerative diseases has garnered widespread attention. Clinical studies have revealed altered miR-132 expression levels in both chronic and acute CNS diseases, positioning miR-132 as a potential biomarker or therapeutic target. An in-depth exploration of miR-132 holds the promise of enhancing our understanding of the mechanisms underlying CNS diseases, thereby offering novel insights and strategies for disease diagnosis and treatment. It is anticipated that this review will assist researchers in recognizing the potential value of miR-132 and in generating innovative ideas for clinical trials related to CNS degenerative diseases.
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Affiliation(s)
- Chenxi Mu
- Basic Medical College, Jiamusi University, Jiamusi 154007, Heilongjiang, China; Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, Jiamusi 154007, Heilongjiang, China
| | - Meng Gao
- Basic Medical College, Jiamusi University, Jiamusi 154007, Heilongjiang, China; Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, Jiamusi 154007, Heilongjiang, China
| | - Weijing Xu
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, Jiamusi 154007, Heilongjiang, China; School of Public Health, Jiamusi University, Jiamusi 154007, Heilongjiang, China
| | - Xun Sun
- Basic Medical College, Jiamusi University, Jiamusi 154007, Heilongjiang, China; Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, Jiamusi 154007, Heilongjiang, China
| | - Tianhao Chen
- Basic Medical College, Jiamusi University, Jiamusi 154007, Heilongjiang, China; Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, Jiamusi 154007, Heilongjiang, China
| | - Hui Xu
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, Jiamusi 154007, Heilongjiang, China.
| | - Hongbin Qiu
- School of Public Health, Jiamusi University, Jiamusi 154007, Heilongjiang, China.
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19
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Ertay A, Ewing RM, Wang Y. Synthetic lethal approaches to target cancers with loss of PTEN function. Genes Dis 2023; 10:2511-2527. [PMID: 37533462 PMCID: PMC7614861 DOI: 10.1016/j.gendis.2022.12.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 12/26/2022] [Accepted: 12/27/2022] [Indexed: 02/05/2023] Open
Abstract
Phosphatase and tensin homolog (PTEN) is a tumour suppressor gene and has a role in inhibiting the oncogenic AKT signalling pathway by dephosphorylating phosphatidylinositol 3,4,5-triphosphate (PIP3) into phosphatidylinositol 4,5-bisphosphate (PIP2). The function of PTEN is regulated by different mechanisms and inactive PTEN results in aggressive tumour phenotype and tumorigenesis. Identifying targeted therapies for inactive tumour suppressor genes such as PTEN has been challenging as it is difficult to restore the tumour suppressor functions. Therefore, focusing on the downstream signalling pathways to discover a targeted therapy for inactive tumour suppressor genes has highlighted the importance of synthetic lethality studies. This review focuses on the potential synthetic lethality genes discovered in PTEN-inactive cancer types. These discovered genes could be potential targeted therapies for PTEN-inactive cancer types and may improve the treatment response rates for aggressive types of cancer.
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Affiliation(s)
- Ayse Ertay
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
| | - Rob M. Ewing
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
- Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
| | - Yihua Wang
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
- Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
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20
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Al-Toubat M, Serrano S, Elshafei A, Koul K, Feibus AH, Balaji KC. Metastatic prostate cancer is associated with distinct higher frequency of genetic mutations at diagnosis. Urol Oncol 2023; 41:455.e7-455.e15. [PMID: 37838503 DOI: 10.1016/j.urolonc.2023.09.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 09/18/2023] [Accepted: 09/22/2023] [Indexed: 10/16/2023]
Abstract
INTRODUCTION AND OBJECTIVES We explored characteristic genetic mutations associated with metastatic prostate cancer (PCa) by comparing next generation sequencing (NGS) data between men with or without metastatic disease at diagnosis. METHODS We queried the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (GENIE) registry for men diagnosed with PCa. Patients were categorized into with (M1) or without metastatic disease (M0) groups. The difference in the frequency of genetic mutations between the two groups and the prognostic significance of the mutations were analyzed using SPSS V28. We included frequency rate of > 5% and P values < 0.05 were considered statistically significant to maintain over 95% true positive detection rate. RESULTS Of a total of 10,580 patients with diagnosis of PCa in the dataset, we selected a study cohort of 1268 patients without missing data; 700 (55.2%) had nonmetastatic PCa, 421 (33.2%) and 147 (11.6%) patients had metastatic castration sensitive and resistant PCa respectively. The median age at diagnosis and serum prostate specific antigen (PSA) level for the entire cohort was 62.8 years (IQR 56.3-68.4) and 8.0 ng/ml (IQR 4.9-20.9) respectively. A vast majority of the cohort were of Caucasian ancestry (89.1%). Of a total of 561 genes sequenced, there were mutations in 79 genes (14.1%). The mutation frequency was significantly higher in M1PCa compared to M0PCa, 35.7% and 23.3%, respectively (P = <0.001). The median tumor mutational burden was also significantly higher in the samples from M1PCa (2.59 mut/MB) compared to M0PCa (1.96 mut/MB) (P < 0.001). Compared to M0PCa patients, M1PCa patients demonstrated significantly higher rate of genetic mutations; TP53 (38.73% vs. 17.71% P < 0.001), PTEN (25.70% vs. 11.71% P < 0.001), AR (17.25% vs. 1.43% P < 0.001), APC (11.8% vs. 4.43% P < 0.001), TMPRSS2 (31.5% vs. 11.14% P < 0.001), ERG (23.59% vs. 13.13% P < 0.001), FOXA1 (17.43% vs. 6.33% P < 0.001), MYC (8.45% vs. 2.29% P < 0.001), RB1 (10.39% vs. 2.43% P < 0.001) and CDK12 (8.45% vs. 1.31% P < 0.001). Of the various cellular signaling pathways, the androgen receptor signaling pathway was most often impacted. In the cohort with M1 disease, compared to men without genetic mutations the men with genetic mutations demonstrated worse survival (P = <0.001, log rank test). Compared to castration sensitive M1 patients, AR (57% vs. 4% P < 0.001), TP53 (50.7% vs. 34% P < 0.001), PTEN (35.2% vs. 22.1% P < 0.001), RB1(23.9% vs. 4.75% P < 0.001) were significantly more frequently mutated in castration resistant M1 patients. In contrast, mutations of SPOP (13.3% vs. 7.9% P < 0.001), FOXA1 (17.6% vs. 5.3% P < 0.001) and CDK12 (12% vs. 6.45% P < 0.001) were significantly more frequently found in castration sensitive M1 patients compared to castration resistant patients. CONCLUSION Patients with M1PCa demonstrated characteristic genetic mutations compared to M0PCa, which most often influenced androgen receptor signaling and is associated with worse survival. In addition, we identified distinct genetic mutations between castration sensitive and resistant M1PCa. These findings may be used to further our understanding and management of men with PCa.
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Affiliation(s)
- Mohammed Al-Toubat
- Department of Urology, University of Florida College of Medicine, Jacksonville, FL
| | - Samuel Serrano
- Department of Urology, University of Florida College of Medicine, Jacksonville, FL
| | - Ahmed Elshafei
- Department of Urology, University of Florida College of Medicine, Jacksonville, FL
| | - Kashyap Koul
- Department of Urology, University of Florida College of Medicine, Jacksonville, FL
| | - Allison H Feibus
- Department of Urology, University of Florida College of Medicine, Jacksonville, FL
| | - K C Balaji
- Department of Urology, University of Florida College of Medicine, Jacksonville, FL.
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21
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Xiao W, Xu Y, Baak JP, Dai J, Jing L, Zhu H, Gan Y, Zheng S. Network module analysis and molecular docking-based study on the mechanism of astragali radix against non-small cell lung cancer. BMC Complement Med Ther 2023; 23:345. [PMID: 37770919 PMCID: PMC10537544 DOI: 10.1186/s12906-023-04148-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 08/31/2023] [Indexed: 09/30/2023] Open
Abstract
BACKGROUND Most lung cancer patients worldwide (stage IV non-small cell lung cancer, NSCLC) have a poor survival: 25%-30% patients die < 3 months. Yet, of those surviving > 3 months, 10%-15% patients survive (very) long. Astragali radix (AR) is an effective traditional Chinese medicine widely used for non-small cell lung cancer (NSCLC). However, the pharmacological mechanisms of AR on NSCLC remain to be elucidated. METHODS Ultra Performance Liquid Chromatography system coupled with Q-Orbitrap HRMS (UPLC-Q-Orbitrap HRMS) was performed for the qualitative analysis of AR components. Then, network module analysis and molecular docking-based approach was conducted to explore underlying mechanisms of AR on NSCLC. The target genes of AR were obtained from four databases including TCMSP (Traditional Chinese Medicine Systems Pharmacology) database, ETCM (The Encyclopedia of TCM) database, HERB (A high-throughput experiment- and reference-guided database of TCM) database and BATMAN-TCM (a Bioinformatics Analysis Tool for Molecular mechanism of TCM) database. NSCLC related genes were screened by GEO (Gene Expression Omnibus) database. The STRING database was used for protein interaction network construction (PIN) of AR-NSCLC shared target genes. The critical PIN were further constructed based on the topological properties of network nodes. Afterwards the hub genes and network modules were analyzed, and enrichment analysis were employed by the R package clusterProfiler. The Autodock Vina was utilized for molecular docking, and the Gromacs was utilized for molecular dynamics simulations Furthermore, the survival analysis was performed based on TCGA (The Cancer Genome Atlas) database. RESULTS Seventy-seven AR components absorbed in blood were obtained. The critical network was constructed with 1447 nodes and 28,890 edges. Based on topological analysis, 6 hub target genes and 7 functional modules were gained. were obtained including TP53, SRC, UBC, CTNNB1, EP300, and RELA. After module analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that AR may exert therapeutic effects on NSCLC by regulating JAK-STAT signaling pathway, PI3K-AKT signaling pathway, ErbB signaling pathway, as well as NFkB signaling pathway. After the intersection calculation of the hub targets and the proteins participated in the above pathways, TP53, SRC, EP300, and RELA were obtained. These proteins had good docking affinity with astragaloside IV. Furthermore, RELA was associated with poor prognosis of NSCLC patients. CONCLUSIONS This study could provide chemical component information references for further researches. The potential pharmacological mechanisms of AR on NSCLC were elucidated, promoting the clinical application of AR in treating NSCLC. RELA was selected as a promising candidate biomarker affecting the prognosis of NSCLC patients.
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Affiliation(s)
- Wenke Xiao
- School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yaxin Xu
- School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Jan P Baak
- Stavanger University Hospital, Stavanger, 4068, Norway
- Dr. Med Jan Baak AS, Tananger, 4056, Norway
| | - Jinrong Dai
- School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Lijia Jing
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Hongxia Zhu
- School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yanxiong Gan
- School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Shichao Zheng
- School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
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22
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Burgon PG, Weldrick JJ, Talab OMSA, Nadeer M, Nomikos M, Megeney LA. Regulatory Mechanisms That Guide the Fetal to Postnatal Transition of Cardiomyocytes. Cells 2023; 12:2324. [PMID: 37759546 PMCID: PMC10528641 DOI: 10.3390/cells12182324] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 09/16/2023] [Accepted: 09/19/2023] [Indexed: 09/29/2023] Open
Abstract
Heart disease remains a global leading cause of death and disability, necessitating a comprehensive understanding of the heart's development, repair, and dysfunction. This review surveys recent discoveries that explore the developmental transition of proliferative fetal cardiomyocytes into hypertrophic postnatal cardiomyocytes, a process yet to be well-defined. This transition is key to the heart's growth and has promising therapeutic potential, particularly for congenital or acquired heart damage, such as myocardial infarctions. Although significant progress has been made, much work is needed to unravel the complex interplay of signaling pathways that regulate cardiomyocyte proliferation and hypertrophy. This review provides a detailed perspective for future research directions aimed at the potential therapeutic harnessing of the perinatal heart transitions.
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Affiliation(s)
- Patrick G. Burgon
- Department of Chemistry and Earth Sciences, College of Arts and Sciences, Qatar University, Doha P.O. Box 2713, Qatar
| | - Jonathan J. Weldrick
- Department of Medicine, Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; (J.J.W.); (L.A.M.)
| | | | - Muhammad Nadeer
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (O.M.S.A.T.)
| | - Michail Nomikos
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (O.M.S.A.T.)
| | - Lynn A. Megeney
- Department of Medicine, Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; (J.J.W.); (L.A.M.)
- Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
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23
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Nikolatou K, Sandilands E, Román‐Fernández A, Cumming EM, Freckmann E, Lilla S, Buetow L, McGarry L, Neilson M, Shaw R, Strachan D, Miller C, Huang DT, McNeish IA, Norman JC, Zanivan S, Bryant DM. PTEN deficiency exposes a requirement for an ARF GTPase module for integrin-dependent invasion in ovarian cancer. EMBO J 2023; 42:e113987. [PMID: 37577760 PMCID: PMC10505920 DOI: 10.15252/embj.2023113987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 07/13/2023] [Accepted: 07/19/2023] [Indexed: 08/15/2023] Open
Abstract
Dysregulation of the PI3K/AKT pathway is a common occurrence in high-grade serous ovarian carcinoma (HGSOC), with the loss of the tumour suppressor PTEN in HGSOC being associated with poor prognosis. The cellular mechanisms of how PTEN loss contributes to HGSOC are largely unknown. We here utilise time-lapse imaging of HGSOC spheroids coupled to a machine learning approach to classify the phenotype of PTEN loss. PTEN deficiency induces PI(3,4,5)P3 -rich and -dependent membrane protrusions into the extracellular matrix (ECM), resulting in a collective invasion phenotype. We identify the small GTPase ARF6 as a crucial vulnerability of HGSOC cells upon PTEN loss. Through a functional proteomic CRISPR screen of ARF6 interactors, we identify the ARF GTPase-activating protein (GAP) AGAP1 and the ECM receptor β1-integrin (ITGB1) as key ARF6 interactors in HGSOC regulating PTEN loss-associated invasion. ARF6 functions to promote invasion by controlling the recycling of internalised, active β1-integrin to maintain invasive activity into the ECM. The expression of the CYTH2-ARF6-AGAP1 complex in HGSOC patients is inversely associated with outcome, allowing the identification of patient groups with improved versus poor outcome. ARF6 may represent a therapeutic vulnerability in PTEN-depleted HGSOC.
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Affiliation(s)
- Konstantina Nikolatou
- School of Cancer SciencesUniversity of GlasgowGlasgowUK
- The CRUK Beatson InstituteGlasgowUK
| | - Emma Sandilands
- School of Cancer SciencesUniversity of GlasgowGlasgowUK
- The CRUK Beatson InstituteGlasgowUK
| | - Alvaro Román‐Fernández
- School of Cancer SciencesUniversity of GlasgowGlasgowUK
- The CRUK Beatson InstituteGlasgowUK
| | - Erin M Cumming
- School of Cancer SciencesUniversity of GlasgowGlasgowUK
- The CRUK Beatson InstituteGlasgowUK
| | - Eva Freckmann
- School of Cancer SciencesUniversity of GlasgowGlasgowUK
- The CRUK Beatson InstituteGlasgowUK
| | | | | | | | | | | | | | | | - Danny T Huang
- School of Cancer SciencesUniversity of GlasgowGlasgowUK
- The CRUK Beatson InstituteGlasgowUK
| | - Iain A McNeish
- Department of Surgery and Cancer, Ovarian Cancer Action Research CentreImperial College LondonLondonUK
| | - James C Norman
- School of Cancer SciencesUniversity of GlasgowGlasgowUK
- The CRUK Beatson InstituteGlasgowUK
| | - Sara Zanivan
- School of Cancer SciencesUniversity of GlasgowGlasgowUK
- The CRUK Beatson InstituteGlasgowUK
| | - David M Bryant
- School of Cancer SciencesUniversity of GlasgowGlasgowUK
- The CRUK Beatson InstituteGlasgowUK
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24
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Feng T, Zhao R, Zhang H, Sun F, Hu J, Wang M, Qi M, Liu L, Gao L, Xiao Y, Zhen J, Chen W, Wang L, Han B. Reciprocal negative feedback regulation of ATF6α and PTEN promotes prostate cancer progression. Cell Mol Life Sci 2023; 80:292. [PMID: 37715829 PMCID: PMC11073217 DOI: 10.1007/s00018-023-04940-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 07/14/2023] [Accepted: 08/04/2023] [Indexed: 09/18/2023]
Abstract
Phosphatase and tensin homolog (PTEN) loss tightly correlates with prostate cancer (PCa) progression and metastasis. Inactivation of PTEN leads to abnormal activation of PI3K/AKT pathway. However, results from clinical trials with AKT inhibitors in PCa have been largely disappointing. Identification of novel regulators of PTEN in PTEN-dysfunctional PCa is urgently needed. Here we demonstrated that the expression level of PTEN is inversely correlated with the signature score of unfolded protein response (UPR) in PCa. Importantly, PTEN suppresses the activity of ATF6α, via interacting to de-phosphorylate ATF6α and consequently inhibiting its nuclear translocation. Conversely, ATF6α promotes the ubiquitination and degradation of PTEN by inducing CHIP expression. Thus, ATF6α and PTEN forms a negative feedback loop during PCa progression. Combination of ATF6α inhibitor with AKT inhibitor suppresses tumor cell proliferation and xenograft growth. Importantly, this study highlighted ATF6α as a therapeutic vulnerability in PTEN dysfunctional PCa.
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Affiliation(s)
- Tingting Feng
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
| | - Ru Zhao
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
- Department of Pathology, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Hanwen Zhang
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
| | - Feifei Sun
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
| | - Jing Hu
- Department of Pathology, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Meng Wang
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
| | - Mei Qi
- Department of Pathology, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Ling Liu
- Department of Pathology, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Lin Gao
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
| | - Yabo Xiao
- School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
| | - Junhui Zhen
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
- Department of Pathology, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Weiwen Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Shandong University, Jinan, Shandong, China
| | - Lin Wang
- Biomedical Sciences College and Shandong Medicinal Biotechnology Centre, NHC Key Laboratory of Biotechnology Drugs, Key Lab for Rare and Uncommon Diseases of Shandong Province, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China.
| | - Bo Han
- The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China.
- Department of Pathology, Qilu Hospital, Shandong University, Jinan, Shandong, China.
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25
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Zhang KK, Burns CM, Skinner ME, Lombard DB, Miller RA, Endicott SJ. PTEN is both an activator and a substrate of chaperone-mediated autophagy. J Cell Biol 2023; 222:e202208150. [PMID: 37418003 PMCID: PMC10327811 DOI: 10.1083/jcb.202208150] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 04/17/2023] [Accepted: 05/26/2023] [Indexed: 07/08/2023] Open
Abstract
PTEN is a crucial negative regulator of the INS/PI3K/AKT pathway and is one of the most commonly mutated tumor suppressors in cancer. Global overexpression (OE) of PTEN in mice shifts metabolism to favor oxidative phosphorylation over glycolysis, reduces fat mass, and extends the lifespan of both sexes. We demonstrate that PTEN regulates chaperone-mediated autophagy (CMA). Using cultured cells and mouse models, we show that PTEN OE enhances CMA, dependent upon PTEN's lipid phosphatase activity and AKT inactivation. Reciprocally, PTEN knockdown reduces CMA, which can be rescued by inhibiting class I PI3K or AKT. Both PTEN and CMA are negative regulators of glycolysis and lipid droplet formation. We show that suppression of glycolysis and lipid droplet formation downstream of PTEN OE depends on CMA activity. Finally, we show that PTEN protein levels are sensitive to CMA and that PTEN accumulates in lysosomes with elevated CMA. Collectively, these data suggest that CMA is both an effector and a regulator of PTEN.
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Affiliation(s)
- Katherine K. Zhang
- College of Literature, Arts, and the Sciences, University of Michigan, Ann Arbor, Ann Arbor, MI, USA
| | - Calvin M. Burns
- Department of Pathology, University of Michigan, Ann Arbor, Ann Arbor, MI, USA
| | - Mary E. Skinner
- Department of Neurology, University of Michigan, Ann Arbor, Ann Arbor, MI, USA
| | - David B. Lombard
- Department of Pathology and Laboratory Medicine, and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Richard A. Miller
- Department of Pathology, University of Michigan, Ann Arbor, Ann Arbor, MI, USA
- Geriatrics Center, University of Michigan, Ann Arbor, Ann Arbor, MI, USA
| | - S. Joseph Endicott
- Department of Pathology, University of Michigan, Ann Arbor, Ann Arbor, MI, USA
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26
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Li X, Miao C, Wang L, Liu M, Chang H, Tian B, Wang D. Estrogen promotes Epithelial ovarian cancer cells proliferation via down-regulating expression and activating phosphorylation of PTEN. Arch Biochem Biophys 2023:109662. [PMID: 37276925 DOI: 10.1016/j.abb.2023.109662] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 05/05/2023] [Accepted: 06/02/2023] [Indexed: 06/07/2023]
Abstract
Epithelial ovarian cancer (EOC) is the most common of cancer death among malignant tumors in women, its occurrence and development are strongly linked to estrogen. Having identified the phosphatase and tensin homologue (PTEN) is a potent tumor suppressor regulating cell proliferation, migration, and survival. Meanwhile, there is a correlation between PTEN protein expression and estrogen receptor expression in EOC. However, no study has amplified on the molecular regulatory mechanism and function between estrogen and PTEN in the development of EOC. In this research, we found that PTEN shows a low expression level in EOC tissues and estrogen decreased PTEN expression via the estrogen receptor 1 (ESR1) in EOC cells. Knockdown of PTEN enhanced the proliferation and migration level of EOC cells driven by estrogen. Moreover, PTEN was also phosphorylated by G protein-coupled receptor 30 (GPR30)-Protein kinase C (PKC) signaling pathway upon estrogen stimulation. Inhibiting the phosphorylation of PTEN weakened the proliferation and migration of estrogen induced-EOC cells estrogen and decreased the phosphorylation of Protein kinase B (AKT) and Mammalian target of rapamycin (mTOR). These results indicated that estrogen decreased PTEN expression level via the ESR1 genomic pathway and phosphorylated PTEN via the GPR30-PKC non-genomic pathway to activate the PI3K/AKT/mTOR signaling pathway, thereby determining the fate of EOC cells.
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Affiliation(s)
- Xiuwen Li
- School of Basic Medical Sciences, Weifang Medical University, Weifang, Shandong, 261053, PR China
| | - Chunlei Miao
- Plastic Surgery Institute, Weifang Medical University, Weifang, Shandong, 261053, PR China
| | - Lin Wang
- Department of Gastroenterology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, 100102, PR China
| | - Mengyan Liu
- Taoyuan People's Hospital, Changde, Hunan, 425700, PR China
| | - Huanchao Chang
- Plastic Surgery Institute, Weifang Medical University, Weifang, Shandong, 261053, PR China
| | - Bo Tian
- Plastic Surgery Institute, Weifang Medical University, Weifang, Shandong, 261053, PR China
| | - Di Wang
- School of Basic Medical Sciences, Weifang Medical University, Weifang, Shandong, 261053, PR China; Plastic Surgery Institute, Weifang Medical University, Weifang, Shandong, 261053, PR China.
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27
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Shang M, Ni L, Shan X, Cui Y, Hu P, Ji Z, Shen L, Zhang Y, Zhou J, Wang T, Yu Q. MTHFD2 reprograms macrophage polarization by inhibiting PTEN. Cell Rep 2023; 42:112481. [PMID: 37149861 DOI: 10.1016/j.celrep.2023.112481] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 02/27/2023] [Accepted: 04/21/2023] [Indexed: 05/09/2023] Open
Abstract
The one-carbon metabolism enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is involved in the regulation of tumor oncogenesis and immune cell functions, but whether it can contribute to macrophage polarization remains elusive. Here, we show that MTHFD2 suppresses polarization of interferon-γ-activated macrophages (M(IFN-γ)) but enhances that of interleukin-4-activated macrophages (M(IL-4)) both in vitro and in vivo. Mechanistically, MTHFD2 interacts with phosphatase and tensin homolog (PTEN) to suppress PTEN's phosphatidylinositol 3,4,5-trisphosphate (PIP3) phosphatase activity and enhance downstream Akt activation, independent of the N-terminal mitochondria-targeting signal of MTHFD2. MTHFD2-PTEN interaction is promoted by IL-4 but not IFN-γ. Furthermore, amino acid residues (aa 215-225) of MTHFD2 directly target PTEN catalytic center (aa 118-141). Residue D168 of MTHFD2 is also critical for regulating PTEN's PIP3 phosphatase activity by affecting MTHFD2-PTEN interaction. Our study suggests a non-metabolic function of MTHFD2 by which MTHFD2 inhibits PTEN activity, orchestrates macrophage polarization, and alters macrophage-mediated immune responses.
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Affiliation(s)
- Man Shang
- Tianjin Institute of Immunology, Division of Infectious Disease, Second Hospital of Tianjin Medical University, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, Tianjin Medical University, Tianjin, 300070, China
| | - Lina Ni
- Tianjin Institute of Immunology, Division of Infectious Disease, Second Hospital of Tianjin Medical University, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, Tianjin Medical University, Tianjin, 300070, China
| | - Xiao Shan
- Tianjin Institute of Immunology, Division of Infectious Disease, Second Hospital of Tianjin Medical University, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, Tianjin Medical University, Tianjin, 300070, China
| | - Yan Cui
- Tianjin Institute of Immunology, Division of Infectious Disease, Second Hospital of Tianjin Medical University, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, Tianjin Medical University, Tianjin, 300070, China
| | - Penghui Hu
- Tianjin Institute of Immunology, Division of Infectious Disease, Second Hospital of Tianjin Medical University, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, Tianjin Medical University, Tianjin, 300070, China
| | - Zemin Ji
- Tianjin Institute of Immunology, Division of Infectious Disease, Second Hospital of Tianjin Medical University, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, Tianjin Medical University, Tianjin, 300070, China
| | - Long Shen
- Tianjin Institute of Immunology, Division of Infectious Disease, Second Hospital of Tianjin Medical University, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, Tianjin Medical University, Tianjin, 300070, China
| | - Yanan Zhang
- Tianjin Institute of Immunology, Division of Infectious Disease, Second Hospital of Tianjin Medical University, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, Tianjin Medical University, Tianjin, 300070, China
| | - Jinxue Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Ting Wang
- The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, Tianjin Medical University, Tianjin 300070, China.
| | - Qiujing Yu
- Tianjin Institute of Immunology, Division of Infectious Disease, Second Hospital of Tianjin Medical University, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, Tianjin Medical University, Tianjin, 300070, China.
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28
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Glover RC, Schwardt NH, Leano SKE, Sanchez ME, Thomason MK, Olive AJ, Reniere ML. A genome-wide screen in macrophages identifies PTEN as required for myeloid restriction of Listeria monocytogenes infection. PLoS Pathog 2023; 19:e1011058. [PMID: 37216395 PMCID: PMC10237667 DOI: 10.1371/journal.ppat.1011058] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 06/02/2023] [Accepted: 05/08/2023] [Indexed: 05/24/2023] Open
Abstract
Listeria monocytogenes (Lm) is an intracellular foodborne pathogen which causes the severe disease listeriosis in immunocompromised individuals. Macrophages play a dual role during Lm infection by both promoting dissemination of Lm from the gastrointestinal tract and limiting bacterial growth upon immune activation. Despite the relevance of macrophages to Lm infection, the mechanisms underlying phagocytosis of Lm by macrophages are not well understood. To identify host factors important for Lm infection of macrophages, we performed an unbiased CRISPR/Cas9 screen which revealed pathways that are specific to phagocytosis of Lm and those that are required for internalization of bacteria generally. Specifically, we discovered the tumor suppressor PTEN promotes macrophage phagocytosis of Lm and L. ivanovii, but not other Gram-positive bacteria. Additionally, we found that PTEN enhances phagocytosis of Lm via its lipid phosphatase activity by promoting adherence to macrophages. Using conditional knockout mice lacking Pten in myeloid cells, we show that PTEN-dependent phagocytosis is important for host protection during oral Lm infection. Overall, this study provides a comprehensive identification of macrophage factors involved in regulating Lm uptake and characterizes the function of one factor, PTEN, during Lm infection in vitro and in vivo. Importantly, these results demonstrate a role for opsonin-independent phagocytosis in Lm pathogenesis and suggest that macrophages play a primarily protective role during foodborne listeriosis.
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Affiliation(s)
- Rochelle C. Glover
- Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America
| | - Nicole H. Schwardt
- Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America
| | - Shania-Kate E. Leano
- Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America
| | - Madison E. Sanchez
- Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America
| | - Maureen K. Thomason
- Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America
| | - Andrew J. Olive
- Department of Microbiology & Molecular Genetics, College of Osteopathic Medicine, Michigan State University, East Lansing, Michigan, United States of America
| | - Michelle L. Reniere
- Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, United States of America
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29
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Malin J, Rosa Birriel C, Hatini V. Pten, Pi3K and PtdIns(3,4,5)P 3 dynamics modulate pulsatile actin branching in Drosophila retina morphogenesis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.17.533017. [PMID: 36993510 PMCID: PMC10055149 DOI: 10.1101/2023.03.17.533017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/19/2023]
Abstract
Epithelial remodeling of the Drosophila retina depends on the pulsatile contraction and expansion of apical contacts between the cells that form its hexagonal lattice. Phosphoinositide PI(3,4,5)P 3 (PIP 3 ) accumulates around tricellular adherens junctions (tAJs) during contact expansion and dissipates during contraction, but with unknown function. Here we found that manipulations of Pten or Pi3K that either decreased or increased PIP 3 resulted in shortened contacts and a disordered lattice, indicating a requirement for PIP 3 dynamics and turnover. These phenotypes are caused by a loss of protrusive branched actin, resulting from impaired activity of the Rac1 Rho GTPase and the WAVE regulatory complex (WRC). We additionally found that during contact expansion, Pi3K moves into tAJs to promote the cyclical increase of PIP 3 in a spatially and temporally precise manner. Thus, dynamic regulation of PIP 3 by Pten and Pi3K controls the protrusive phase of junctional remodeling, which is essential for planar epithelial morphogenesis.
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30
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Tonks NK. Protein Tyrosine Phosphatases: Mighty oaks from little acorns grow. IUBMB Life 2023; 75:337-352. [PMID: 36971473 PMCID: PMC10254075 DOI: 10.1002/iub.2716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 02/23/2023] [Indexed: 03/29/2023]
Abstract
In October 2020, we were finally able to gather for a celebration of Eddy Fischer's 100th birthday. As with many other events, COVID had disrupted and restricted preparations for the gathering, which ultimately was held via ZOOM. Nevertheless, it was a wonderful opportunity to share a day with Eddy, an exceptional scientist and true renaissance man, and to appreciate his stellar contributions to science. Eddy Fischer, together with Ed Krebs, was responsible for the discovery of reversible protein phosphorylation, which launched the entire field of signal transduction. The importance of this seminal work is now being felt throughout the biotechnology industry with the development of drugs that target protein kinases, which have transformed the treatment of a wide array of cancers. I was privileged to have worked with Eddy both as a postdoc and a junior faculty member, during which time we laid the foundations for our current understanding of the protein tyrosine phosphatase (PTP) family of enzymes and their importance as critical regulators of signal transduction. This tribute to Eddy is based upon the talk I presented at the event, giving a personal perspective on Eddy's influence on my career, our early research efforts together in this area, and how the field has developed since then.
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Affiliation(s)
- Nicholas K Tonks
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
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Wijayaratna D, Ratnayake K, Ubeysinghe S, Kankanamge D, Tennakoon M, Karunarathne A. The spatial distribution of GPCR and Gβγ activity across a cell dictates PIP3 dynamics. Sci Rep 2023; 13:2771. [PMID: 36797332 PMCID: PMC9935898 DOI: 10.1038/s41598-023-29639-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 02/08/2023] [Indexed: 02/18/2023] Open
Abstract
Phosphatidylinositol (3,4,5) trisphosphate (PIP3) is a plasma membrane-bound signaling phospholipid involved in many cellular signaling pathways that control crucial cellular processes and behaviors, including cytoskeleton remodeling, metabolism, chemotaxis, and apoptosis. Therefore, defective PIP3 signaling is implicated in various diseases, including cancer, diabetes, obesity, and cardiovascular diseases. Upon activation by G protein-coupled receptors (GPCRs) or receptor tyrosine kinases (RTKs), phosphoinositide-3-kinases (PI3Ks) phosphorylate phosphatidylinositol (4,5) bisphosphate (PIP2), generating PIP3. Though the mechanisms are unclear, PIP3 produced upon GPCR activation attenuates within minutes, indicating a tight temporal regulation. Our data show that subcellular redistributions of G proteins govern this PIP3 attenuation when GPCRs are activated globally, while localized GPCR activation induces sustained subcellular PIP3. Interestingly the observed PIP3 attenuation was Gγ subtype-dependent. Considering distinct cell-tissue-specific Gγ expression profiles, our findings not only demonstrate how the GPCR-induced PIP3 response is regulated depending on the GPCR activity gradient across a cell, but also show how diversely cells respond to spatial and temporal variability of external stimuli.
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Affiliation(s)
- Dhanushan Wijayaratna
- grid.267337.40000 0001 2184 944XDepartment of Chemistry and Biochemistry, The University of Toledo, Toledo, OH 43606 USA ,grid.262962.b0000 0004 1936 9342Department of Chemistry, Saint Louis University, 3501 Laclede Avenue, Saint Louis, MO 63103 USA
| | - Kasun Ratnayake
- grid.267337.40000 0001 2184 944XDepartment of Chemistry and Biochemistry, The University of Toledo, Toledo, OH 43606 USA
| | - Sithurandi Ubeysinghe
- grid.267337.40000 0001 2184 944XDepartment of Chemistry and Biochemistry, The University of Toledo, Toledo, OH 43606 USA ,grid.262962.b0000 0004 1936 9342Department of Chemistry, Saint Louis University, 3501 Laclede Avenue, Saint Louis, MO 63103 USA
| | - Dinesh Kankanamge
- grid.267337.40000 0001 2184 944XDepartment of Chemistry and Biochemistry, The University of Toledo, Toledo, OH 43606 USA ,grid.4367.60000 0001 2355 7002Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO 63110 USA
| | - Mithila Tennakoon
- grid.267337.40000 0001 2184 944XDepartment of Chemistry and Biochemistry, The University of Toledo, Toledo, OH 43606 USA ,grid.262962.b0000 0004 1936 9342Department of Chemistry, Saint Louis University, 3501 Laclede Avenue, Saint Louis, MO 63103 USA
| | - Ajith Karunarathne
- Department of Chemistry and Biochemistry, The University of Toledo, Toledo, OH, 43606, USA. .,Department of Chemistry, Saint Louis University, 3501 Laclede Avenue, Saint Louis, MO, 63103, USA.
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Langdon CG. Nuclear PTEN's Functions in Suppressing Tumorigenesis: Implications for Rare Cancers. Biomolecules 2023; 13:biom13020259. [PMID: 36830628 PMCID: PMC9953540 DOI: 10.3390/biom13020259] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/25/2023] [Accepted: 01/28/2023] [Indexed: 01/31/2023] Open
Abstract
Phosphatase and tensin homolog (PTEN) encodes a tumor-suppressive phosphatase with both lipid and protein phosphatase activity. The tumor-suppressive functions of PTEN are lost through a variety of mechanisms across a wide spectrum of human malignancies, including several rare cancers that affect pediatric and adult populations. Originally discovered and characterized as a negative regulator of the cytoplasmic, pro-oncogenic phosphoinositide-3-kinase (PI3K) pathway, PTEN is also localized to the nucleus where it can exert tumor-suppressive functions in a PI3K pathway-independent manner. Cancers can usurp the tumor-suppressive functions of PTEN to promote oncogenesis by disrupting homeostatic subcellular PTEN localization. The objective of this review is to describe the changes seen in PTEN subcellular localization during tumorigenesis, how PTEN enters the nucleus, and the spectrum of impacts and consequences arising from disrupted PTEN nuclear localization on tumor promotion. This review will highlight the immediate need in understanding not only the cytoplasmic but also the nuclear functions of PTEN to gain more complete insights into how important PTEN is in preventing human cancers.
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Affiliation(s)
- Casey G. Langdon
- Department of Pediatrics, Darby Children’s Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA; ; Tel.: +1-(843)-792-9289
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
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PTEN phosphatase inhibits metastasis by negatively regulating the Entpd5/IGF1R pathway through ATF6. iScience 2023; 26:106070. [PMID: 36824269 PMCID: PMC9942123 DOI: 10.1016/j.isci.2023.106070] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 12/01/2022] [Accepted: 01/23/2023] [Indexed: 01/27/2023] Open
Abstract
PTEN encodes a tumor suppressor with lipid and protein phosphatase activities whose dysfunction has been implicated in melanomagenesis; less is known about how its phosphatases regulate melanoma metastasis. We demonstrate that PTEN expression negatively correlates with metastatic progression in human melanoma samples and a PTEN-deficient mouse melanoma model. Wildtype PTEN expression inhibited melanoma cell invasiveness and metastasis in a dose-dependent manner, behaviors that specifically required PTEN protein phosphatase activity. PTEN phosphatase activity regulated metastasis through Entpd5. Entpd5 knockdown reduced metastasis and IGF1R levels while promoting ER stress. In contrast, Entpd5 overexpression promoted metastasis and enhanced IGF1R levels while reducing ER stress. Moreover, Entpd5 expression was regulated by the ER stress sensor ATF6. Altogether, our data indicate that PTEN phosphatase activity inhibits metastasis by negatively regulating the Entpd5/IGF1R pathway through ATF6, thereby identifying novel candidate therapeutic targets for the treatment of PTEN mutant melanoma.
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Cetintas VB, Duzgun Z, Akalin T, Ozgiray E, Dogan E, Yildirim Z, Akinturk N, Biceroglu H, Ertan Y, Kosova B. Molecular dynamic simulation and functional analysis of pathogenic PTEN mutations in glioblastoma. J Biomol Struct Dyn 2023; 41:11471-11483. [PMID: 36591942 DOI: 10.1080/07391102.2022.2162582] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 12/20/2022] [Indexed: 01/03/2023]
Abstract
PTEN, a dual-phosphatase and scaffold protein, is one of the most commonly mutated tumour suppressor gene across various cancer types in human. The aim of this study therefore was to investigate the stability, structural and functional effects, and pathogenicity of 12 missense PTEN mutations (R15S, E18G, G36R, N49I, Y68H, I101T, C105F, D109N, V133I, C136Y, R173C and N276S) found by next generation sequencing of the PTEN gene in tissue samples obtained from glioblastoma patients. Computational tools and molecular dynamic simulation programs were used to identify the deleterious effects of these mutations. Furthermore, PTEN mRNA and protein expression levels were evaluated by qRT-PCR, Western Blot, and immunohistochemistry staining methods. Various computational tools predicted strong deleterious effects for the G36R, C105F, C136Y and N276S mutations. Molecular dynamic simulation revealed a significant decrease in protein stability for the Y68H and N276S mutations when compared with the wild type protein; whereas, C105F, D109N, V133I and R173C showed partial stability reduction. Significant residual fluctuations were observed in the R15S, N49I and C136Y mutations and radius of gyration graphs revealed the most compact structure for D109N and least for C136Y. In summary, our study is the first one to show the presence of PTEN E18G, N49I, D109N and N276S mutations in glioblastoma patients; where, D109N is neutral and N276S is a damaging and disease-associated mutation.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
| | - Zekeriya Duzgun
- Department of Medical Biology, Giresun University Faculty of Medicine, Giresun, Turkey
| | - Taner Akalin
- Department of Pathology, Ege University Faculty of Medicine, Izmir, Turkey
| | - Erkin Ozgiray
- Department of Neurosurgery, Ege University Faculty of Medicine, Izmir, Turkey
| | - Eda Dogan
- Department of Medical Biology, Ege University Faculty of Medicine, Izmir, Turkey
| | - Zafer Yildirim
- Department of Medical Biology, Ege University Faculty of Medicine, Izmir, Turkey
| | - Nevhis Akinturk
- Department of Neurosurgery, Ege University Faculty of Medicine, Izmir, Turkey
| | - Huseyin Biceroglu
- Department of Neurosurgery, Ege University Faculty of Medicine, Izmir, Turkey
| | - Yesim Ertan
- Department of Pathology, Ege University Faculty of Medicine, Izmir, Turkey
| | - Buket Kosova
- Department of Medical Biology, Ege University Faculty of Medicine, Izmir, Turkey
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McMurtry V, Canberk S, Deftereos G. Molecular testing in fine-needle aspiration of thyroid nodules. Diagn Cytopathol 2023; 51:36-50. [PMID: 36480743 DOI: 10.1002/dc.25035] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 07/20/2022] [Accepted: 07/22/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Thyroid nodules are commonly faced by clinicians as palpable nodules or incidentally identified on imaging. Nodules that are found to be suspicious by imaging can be biopsied by fine needle aspiration, which can yield material for molecular testing to refine the diagnosis. METHODS The current literature concerning molecular testing in thyroid nodules including available commercial assays was reviewed and summarized. RESULTS/CONCLUSIONS Commonly encountered alterations include mutations in RAS, BRAF, TERT promoter, PTEN, and DICER1 as well as fusions of RET, ALK, PAX8-PPARγ, and NTRK. This article provides a summary of these molecular alterations, commercially available molecular assays, and general considerations for thyroid epithelial malignancies and benign thyroid nodules.
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Affiliation(s)
- Valarie McMurtry
- Department of Pathology, University of Utah, Salt Lake City, Utah, USA.,ARUP Institute for Experimental Pathology, Salt Lake City, Utah, USA
| | - Sule Canberk
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal.,Abel Salazar Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal
| | - Georgios Deftereos
- Department of Pathology, University of Utah, Salt Lake City, Utah, USA.,ARUP Institute for Experimental Pathology, Salt Lake City, Utah, USA
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Scalia P, Williams SJ, Fujita-Yamaguchi Y, Giordano A. Cell cycle control by the insulin-like growth factor signal: at the crossroad between cell growth and mitotic regulation. Cell Cycle 2023; 22:1-37. [PMID: 36005738 PMCID: PMC9769454 DOI: 10.1080/15384101.2022.2108117] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
In proliferating cells and tissues a number of checkpoints (G1/S and G2/M) preceding cell division (M-phase) require the signal provided by growth factors present in serum. IGFs (I and II) have been demonstrated to constitute key intrinsic components of the peptidic active fraction of mammalian serum. In vivo genetic ablation studies have shown that the cellular signal triggered by the IGFs through their cellular receptors represents a non-replaceable requirement for cell growth and cell cycle progression. Retroactive and current evaluation of published literature sheds light on the intracellular circuitry activated by these factors providing us with a better picture of the pleiotropic mechanistic actions by which IGFs regulate both cell size and mitogenesis under developmental growth as well as in malignant proliferation. The present work aims to summarize the cumulative knowledge learned from the IGF ligands/receptors and their intracellular signaling transducers towards control of cell size and cell-cycle with particular focus to their actionable circuits in human cancer. Furthermore, we bring novel perspectives on key functional discriminants of the IGF growth-mitogenic pathway allowing re-evaluation on some of its signal components based upon established evidences.
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Affiliation(s)
- Pierluigi Scalia
- ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA, USA, Caltanissetta, Italy,CST, Biology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, United states,CONTACT Pierluigi Scalia ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA9102, USA
| | - Stephen J Williams
- ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA, USA, Caltanissetta, Italy,CST, Biology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, United states
| | - Yoko Fujita-Yamaguchi
- Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Antonio Giordano
- ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA, USA, Caltanissetta, Italy,School of Medical Biotechnology, University of Siena, Italy
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Li Q, Zhang W. Progress in Anticancer Drug Development Targeting Ubiquitination-Related Factors. Int J Mol Sci 2022; 23:ijms232315104. [PMID: 36499442 PMCID: PMC9737479 DOI: 10.3390/ijms232315104] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/24/2022] [Accepted: 10/26/2022] [Indexed: 12/05/2022] Open
Abstract
Ubiquitination is extensively involved in critical signaling pathways through monitoring protein stability, subcellular localization, and activity. Dysregulation of this process results in severe diseases including malignant cancers. To develop drugs targeting ubiquitination-related factors is a hotspot in research to realize better therapy of human diseases. Ubiquitination comprises three successive reactions mediated by Ub-activating enzyme E1, Ub-conjugating enzyme E2, and Ub ligase E3. As expected, multiple ubiquitination enzymes have been highlighted as targets for anticancer drug development due to their dominant effect on tumorigenesis and cancer progression. In this review, we discuss recent progresses in anticancer drug development targeting enzymatic machinery components.
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Targeting PTEN Regulation by Post Translational Modifications. Cancers (Basel) 2022; 14:cancers14225613. [PMID: 36428706 PMCID: PMC9688753 DOI: 10.3390/cancers14225613] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 11/07/2022] [Accepted: 11/11/2022] [Indexed: 11/17/2022] Open
Abstract
Phosphatidylinositol-3,4,5-triphosphate (PIP3) is a lipidic second messenger present at very low concentrations in resting normal cells. PIP3 levels, though, increase quickly and transiently after growth factor addition, upon activation of phosphatidylinositol 3-kinase (PI3-kinase). PIP3 is required for the activation of intracellular signaling pathways that induce cell proliferation, cell migration, and survival. Given the critical role of this second messenger for cellular responses, PIP3 levels must be tightly regulated. The lipid phosphatase PTEN (phosphatase and tensin-homolog in chromosome 10) is the phosphatase responsible for PIP3 dephosphorylation to PIP2. PTEN tumor suppressor is frequently inactivated in endometrium and prostate carcinomas, and also in glioblastoma, illustrating the contribution of elevated PIP3 levels for cancer development. PTEN biological activity can be modulated by heterozygous gene loss, gene mutation, and epigenetic or transcriptional alterations. In addition, PTEN can also be regulated by post-translational modifications. Acetylation, oxidation, phosphorylation, sumoylation, and ubiquitination can alter PTEN stability, cellular localization, or activity, highlighting the complexity of PTEN regulation. While current strategies to treat tumors exhibiting a deregulated PI3-kinase/PTEN axis have focused on PI3-kinase inhibition, a better understanding of PTEN post-translational modifications could provide new therapeutic strategies to restore PTEN action in PIP3-dependent tumors.
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Banerjee T, Biswas D, Pal DS, Miao Y, Iglesias PA, Devreotes PN. Spatiotemporal dynamics of membrane surface charge regulates cell polarity and migration. Nat Cell Biol 2022; 24:1499-1515. [PMID: 36202973 PMCID: PMC10029748 DOI: 10.1038/s41556-022-00997-7] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 08/18/2022] [Indexed: 12/12/2022]
Abstract
During cell migration and polarization, numerous signal transduction and cytoskeletal components self-organize to generate localized protrusions. Although biochemical and genetic analyses have delineated many specific interactions, how the activation and localization of so many different molecules are spatiotemporally orchestrated at the subcellular level has remained unclear. Here we show that the regulation of negative surface charge on the inner leaflet of the plasma membrane plays an integrative role in the molecular interactions. Surface charge, or zeta potential, is transiently lowered at new protrusions and within cortical waves of Ras/PI3K/TORC2/F-actin network activation. Rapid alterations of inner leaflet anionic phospholipids-such as PI(4,5)P2, PI(3,4)P2, phosphatidylserine and phosphatidic acid-collectively contribute to the surface charge changes. Abruptly reducing the surface charge by recruiting positively charged optogenetic actuators was sufficient to trigger the entire biochemical network, initiate de novo protrusions and abrogate pre-existing polarity. These effects were blocked by genetic or pharmacological inhibition of key signalling components such as AKT and PI3K/TORC2. Conversely, increasing the negative surface charge deactivated the network and locally suppressed chemoattractant-induced protrusions or subverted EGF-induced ERK activation. Computational simulations involving excitable biochemical networks demonstrated that slight changes in feedback loops, induced by recruitment of the charged actuators, could lead to outsized effects on system activation. We propose that key signalling network components act on, and are in turn acted upon, by surface charge, closing feedback loops, which bring about the global-scale molecular self-organization required for spontaneous protrusion formation, cell migration and polarity establishment.
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Affiliation(s)
- Tatsat Banerjee
- Department of Cell Biology and Center for Cell Dynamics, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
- Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Debojyoti Biswas
- Department of Electrical and Computer Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Dhiman Sankar Pal
- Department of Cell Biology and Center for Cell Dynamics, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Yuchuan Miao
- Department of Cell Biology and Center for Cell Dynamics, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
- Department of Biological Chemistry, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Pablo A Iglesias
- Department of Cell Biology and Center for Cell Dynamics, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
- Department of Electrical and Computer Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Peter N Devreotes
- Department of Cell Biology and Center for Cell Dynamics, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
- Department of Biological Chemistry, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
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Sueta A, Takeno M, Goto-Yamaguchi L, Tomiguchi M, Inao T, Yamamoto-Ibusuki M, Yamamoto Y. A progressive and refractory case of breast cancer with Cowden syndrome. World J Surg Oncol 2022; 20:279. [PMID: 36057718 PMCID: PMC9440557 DOI: 10.1186/s12957-022-02745-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 08/02/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Cowden syndrome is a rare autosomal-dominant disease with a high risk of malignant tumors of the breast, commonly caused by germline mutations in the PTEN gene. Most breast cancers related to Cowden syndrome showed typically a slow-growing and favorable clinical course. Here, we report a progressive case of triple-negative breast cancer in a patient who was diagnosed with Cowden syndrome. CASE PRESENTATION A 35-year-old female with breast cancer was referred to our hospital. Histopathological examination of the tumor showed that it was triple-negative breast cancer with high proliferation marker. Preoperative positron emission tomography-computed tomography showed abnormal uptake in the left cerebellar hemisphere in addition to the right breast and axillary lymph node. Brain T2-weighted magnetic resonance imaging revealed hyperintense bands in the left cerebellar hemisphere lesion, which demonstrated a "tiger-stripe" appearance. The patient's mother had died of endometrial cancer. Subsequently, she underwent genetic testing, leading to a diagnosis of Cowden syndrome with a pathogenic variant c.823_840del.18 at exon 8 in PTEN. She was treated with neoadjuvant chemotherapy of eribulin and cyclophosphamide followed by adriamycin and cyclophosphamide. However, her tumors increased after these treatments. She was immediately surgically treated and received adjuvant chemotherapy of capecitabine. Unfortunately, the cancer recurred in the lung nine months after surgery. We then administered paclitaxel and bevacizumab therapy, but the disease rapidly progressed. Consequently, the patient died due to breast cancer about three months after recurrence. CONCLUSION We report an aggressive case of cancer with Cowden syndrome which was resistant to standard chemotherapy. Alteration of the phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin pathway due to inactivating PTEN protein may be associated with chemoresistance and serves as a candidate for therapeutic intervention in PTEN-related cancers.
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Affiliation(s)
- Aiko Sueta
- Department of Breast and Endocrine Surgery, Kumamoto University Graduate School of Medical Science, 1-1-1, Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Masako Takeno
- Department of Breast and Endocrine Surgery, Kumamoto University Graduate School of Medical Science, 1-1-1, Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Lisa Goto-Yamaguchi
- Department of Breast and Endocrine Surgery, Kumamoto University Graduate School of Medical Science, 1-1-1, Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Mai Tomiguchi
- Department of Breast and Endocrine Surgery, Kumamoto University Graduate School of Medical Science, 1-1-1, Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Toko Inao
- Department of Breast and Endocrine Surgery, Kumamoto University Graduate School of Medical Science, 1-1-1, Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Mutsuko Yamamoto-Ibusuki
- Department of Breast and Endocrine Surgery, Kumamoto University Graduate School of Medical Science, 1-1-1, Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Yutaka Yamamoto
- Department of Breast and Endocrine Surgery, Kumamoto University Graduate School of Medical Science, 1-1-1, Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
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Sun Y, Zhang H, Meng J, Guo F, Ren D, Wu H, Jin X. S-palmitoylation of PCSK9 induces sorafenib resistance in liver cancer by activating the PI3K/AKT pathway. Cell Rep 2022; 40:111194. [PMID: 35977495 DOI: 10.1016/j.celrep.2022.111194] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 05/10/2022] [Accepted: 07/20/2022] [Indexed: 11/03/2022] Open
Abstract
Sorafenib is currently the first-line treatment for advanced hepatocellular carcinoma (HCC). However, sorafenib resistance remains a significant challenge. Aberrant AKT signaling activation is a crucial mechanism driving sorafenib resistance in HCC. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a vital role in antitumor immune responses. In this study, we demonstrate that aberrant PCSK9 upregulation promotes cell proliferation and sorafenib resistance in HCC by inducing AKT-S473 phosphorylation. After palmitoylation at cysteine 600, the binding affinity between PCSK9 and tensin homolog (PTEN) is dramatically increased, inducing lysosome-mediated PTEN degradation and subsequent AKT activation. We identify zinc finger DHHC-type palmitoyltransferase 16 (ZDHHC16) as a palmitoyltransferase that promotes PCSK9 palmitoylation at cysteine 600. We also develop a biologically active PCSK9-derived peptide that competitively inhibits PCSK9 palmitoylation, suppressing AKT phosphorylation and augmenting the antitumor effects of sorafenib in HCC.
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Affiliation(s)
- Yan Sun
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Huan Zhang
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Junpeng Meng
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Department of General Surgery, the Second Hospital of Shanxi Medical University, Taiyuan, 030001 Shanxi, China
| | - Feng Guo
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Dianyun Ren
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Heshui Wu
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Xin Jin
- Department of Urology, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Uro-Oncology Institute of Central South University, Changsha, Hunan 410011, China.
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PTEN Dual Lipid- and Protein-Phosphatase Function in Tumor Progression. Cancers (Basel) 2022; 14:cancers14153666. [PMID: 35954330 PMCID: PMC9367293 DOI: 10.3390/cancers14153666] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/17/2022] [Accepted: 07/22/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a multifunctional tumor suppressor with protein- and lipid-phosphatase activities. The inactivation of PTEN is commonly found in all human cancers and is correlated with tumor progression. PTEN-lipid-phosphatase activity has been well documented to dephosphorylate phosphatidylinositol-3, 4, 5-phosphate (PIP3), which hinders cell growth and survival by dampening the PI3K and AKT signaling activity. PTEN-protein-phosphatase activity is less well studied and understood. Recent studies have reported that PTEN-protein-phosphatase activity dephosphorylates the different proteins and acts in various cell functions. We here review the PTEN mutations and protein-phosphatase substrates in tumor progression. We aim to address the gap in our understanding as to how PTEN protein phosphatase contributes to its tumor-suppression functions. Abstract PTEN is the second most highly mutated tumor suppressor in cancer, following only p53. The PTEN protein functions as a phosphatase with lipid- and protein-phosphatase activity. PTEN-lipid-phosphatase activity dephosphorylates PIP3 to form PIP2, and it then antagonizes PI3K and blocks the activation of AKT, while its protein-phosphatase activity dephosphorylates different protein substrates and plays various roles in tumorigenesis. Here, we review the PTEN mutations and protein-phosphatase substrates in tumorigenesis and metastasis. Our purpose is to clarify how PTEN protein phosphatase contributes to its tumor-suppressive functions through PI3K-independent activities.
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Ceyhan Y, Zhang M, Sandoval CG, Agoulnik AI, Agoulnik IU. Expression pattern and the roles of phosphatidylinositol phosphatases in testis. Biol Reprod 2022; 107:902-915. [PMID: 35766372 DOI: 10.1093/biolre/ioac132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 06/02/2022] [Accepted: 06/20/2022] [Indexed: 11/13/2022] Open
Abstract
Phosphoinositides (PIs) are relatively rare lipid components of the cellular membranes. Their homeostasis is tightly controlled by specific PI kinases and phosphatases. PIs play essential roles in cellular signaling, cytoskeletal organization, and secretory processes in various diseases and normal physiology. Gene targeting experiments strongly suggest that in mice with deficiency of several PI phosphatases such as Pten, Mtmrs, Inpp4b, and Inpp5b, spermatogenesis is affected, resulting in partial or complete infertility. Similarly, in men, loss of several of the PIP phosphatases is observed in infertility characterized by the lack of mature sperm. Using available gene expression databases, we compare expression of known PI phosphatases in various testicular cell types, infertility patients, and mouse age-dependent testicular gene expression, and discuss their potential roles in testis physiology and spermatogenesis.
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Affiliation(s)
- Yasemin Ceyhan
- Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
| | - Manqi Zhang
- Department of Medicine, Duke University, Durham, NC, USA
| | - Carlos G Sandoval
- Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA.,New York University Grossman School of Medicine, New York, NY, USA
| | - Alexander I Agoulnik
- Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA.,Biomolecular Sciences Institute, Florida International University, Miami, FL, USA
| | - Irina U Agoulnik
- Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA.,Biomolecular Sciences Institute, Florida International University, Miami, FL, USA.,Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
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Conciatori F, Salvati E, Ciuffreda L, Shirasawa S, Falcone I, Cognetti F, Ferretti G, Zeuli M, Del Bufalo D, Bazzichetto C, Milella M. Fibroblast-Induced Paradoxical PI3K Pathway Activation in PTEN-Competent Colorectal Cancer: Implications for Therapeutic PI3K/mTOR Inhibition. Front Oncol 2022; 12:862806. [PMID: 35719951 PMCID: PMC9203999 DOI: 10.3389/fonc.2022.862806] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 04/28/2022] [Indexed: 12/12/2022] Open
Abstract
Purpose Tumor-microenvironment interactions are important determinants of drug resistance in colorectal cancer (CRC). We, therefore, set out to understand how interactions between genetically characterized CRC cells and stromal fibroblasts might influence response to molecularly targeted inhibitors. Techniques Sensitivity to PI3K/AKT/mTOR pathway inhibitors of CRC cell lines, with known genetic background, was investigated under different culture conditions [serum-free medium, fibroblasts’ conditioned medium (CM), direct co-culture]. Molecular pathway activation was monitored using Western Blot analysis. Immunoprecipitation was used to detect specific mTOR complex activation. Immunofluorescence was used to analyze cellular PTEN distribution, while different mutant PTEN plasmids were used to map the observed function to specific PTEN protein domains. Results Exposure to fibroblast-CM resulted in increased growth-inhibitory response to double PI3K/mTOR inhibitors in PTEN-competent CRC cell lines harboring KRAS and PI3K mutations. Such functional effect was attributable to fibroblast-CM induced paradoxical PI3K/mTORC1 pathway activation, occurring in the presence of a functional PTEN protein. At a molecular level, fibroblast-CM induced C-tail phosphorylation and cytoplasmic redistribution of the PTEN protein, thereby impairing its lipid phosphatase function and favored the formation of active, RAPTOR-containing, mTORC1 complexes. However, PTEN’s lipid phosphatase function appeared to be dispensable, while complex protein-protein interactions, also involving PTEN/mTOR co-localization and subcellular distribution, were crucial for both mTORC1 activation and sensitivity to double PI3K/mTOR inhibitors. Data Interpretation Microenvironmental cues, in particular soluble factors produced by stromal fibroblasts, profoundly influence PI3K pathway signaling and functional response to specific inhibitors in CRC cells, depending on their mutational background and PTEN status.
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Affiliation(s)
- Fabiana Conciatori
- Medical Oncology 1, Regina Elena National Cancer Institute (IRCCS), Rome, Italy.,Preclinical Models and New Therapeutic Agents Unit, Regina Elena National Cancer Institute (IRCCS), Rome, Italy
| | - Erica Salvati
- Institute of Molecular Biology and Pathology -National Research Council (BPM-CNR), Rome, Italy
| | - Ludovica Ciuffreda
- Department of Research, Advanced Diagnostics, and Technological Innovation (SAFU), Regina Elena National Cancer Institute (IRCCS), Rome, Italy
| | - Senji Shirasawa
- Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka, Japan
| | - Italia Falcone
- Department of Research, Advanced Diagnostics, and Technological Innovation (SAFU), Regina Elena National Cancer Institute (IRCCS), Rome, Italy
| | - Francesco Cognetti
- Medical Oncology 1, Regina Elena National Cancer Institute (IRCCS), Rome, Italy
| | - Gianluigi Ferretti
- Medical Oncology 1, Regina Elena National Cancer Institute (IRCCS), Rome, Italy
| | - Massimo Zeuli
- Medical Oncology 1, Regina Elena National Cancer Institute (IRCCS), Rome, Italy
| | - Donatella Del Bufalo
- Preclinical Models and New Therapeutic Agents Unit, Regina Elena National Cancer Institute (IRCCS), Rome, Italy
| | - Chiara Bazzichetto
- Medical Oncology 1, Regina Elena National Cancer Institute (IRCCS), Rome, Italy.,Preclinical Models and New Therapeutic Agents Unit, Regina Elena National Cancer Institute (IRCCS), Rome, Italy
| | - Michele Milella
- Section of Oncology, Department of Medicine, University of Verona School of Medicine and Verona University Hospital Trust, Verona, Italy
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Wittes J, Greenwald I. Genetic analysis of DAF-18/PTEN missense mutants for the ability to maintain quiescence of the somatic gonad and germ line in Caenorhabditis elegans dauer larvae. G3 (BETHESDA, MD.) 2022; 12:jkac093. [PMID: 35451467 PMCID: PMC9157151 DOI: 10.1093/g3journal/jkac093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 04/04/2022] [Indexed: 11/13/2022]
Abstract
The mammalian tumor suppressor PTEN has well-established lipid phosphatase and protein phosphatase activities. DAF-18, the Caenorhabditis elegans ortholog of PTEN, has a high degree of conservation in the catalytic domain, and human PTEN complements a null allele of daf-18, suggesting conserved protein function. Insights gleaned from studies of mammalian PTEN have been applied to studies of DAF-18 in C. elegans, including predicted enzymatic properties of mutants. Here, we characterize DAF-18 missense mutants previously treated as selectively disrupting either protein or lipid phosphatase activity in genetic assays to connect distinct phenotypes to specific enzymatic activities of DAF-18/PTEN. We analyze the ability of these mutants to maintain quiescence of the somatic gonad and germ line in dauer larvae, a state of diapause during which development is suspended. We show that transgenes expressing either the putative lipid phosphatase-deficient or putative protein phosphatase-deficient form fail to complement a daf-18 null allele, and that the corresponding homozygous endogenous missense mutant alleles fail to maintain developmental quiescence. We also show that the endogenous daf-18 missense alleles fail to complement each other, suggesting that one or both of the missense forms are not activity-selective. Furthermore, homozygous daf-18 missense mutants have a more severe phenotype than a daf-18 null mutant, suggesting the presence of functionally compromised mutant DAF-18 is more deleterious than the absence of DAF-18. We discuss how these genetic properties complicate the interpretation of genetic assays to associate specific enzymatic activities with specific phenotypes.
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Affiliation(s)
- Julia Wittes
- Department of Biological Sciences, Columbia University, New York, NY 10027, USA
| | - Iva Greenwald
- Department of Biological Sciences, Columbia University, New York, NY 10027, USA
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Chen J, Tang LY, Powell ME, Jordan JM, Baugh LR. Genetic analysis of daf-18/PTEN missense mutants for starvation resistance and developmental regulation during Caenorhabditis elegans L1 arrest. G3 (BETHESDA, MD.) 2022; 12:jkac092. [PMID: 35451480 PMCID: PMC9157142 DOI: 10.1093/g3journal/jkac092] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 04/14/2022] [Indexed: 02/06/2023]
Abstract
Mutations in the well-known tumor suppressor PTEN are observed in many cancers. PTEN is a dual-specificity phosphatase that harbors lipid and protein-phosphatase activities. The Caenorhabditis elegans PTEN ortholog is daf-18, which has pleiotropic effects on dauer formation, aging, starvation resistance, and development. Function of 3 daf-18 point-mutants, G174E, D137A, and C169S, had previously been investigated using high-copy transgenes in a daf-18 null background. These alleles were generated based on their mammalian counterparts and were treated as though they specifically disrupt lipid or protein-phosphatase activity, or both, respectively. Here, we investigated these alleles using genome editing of endogenous daf-18. We assayed 3 traits relevant to L1 starvation resistance, and we show that each point mutant is essentially as starvation-sensitive as a daf-18 null mutant. Furthermore, we show that G174E and D137A do not complement each other, suggesting overlapping effects on lipid and protein-phosphatase activity. We also show that each allele has strong effects on nucleocytoplasmic localization of DAF-16/FoxO and dauer formation, both of which are regulated by PI3K signaling, similar to a daf-18 null allele. In addition, each allele also disrupts M-cell quiescence during L1 starvation, though D137A has a weaker effect than the other alleles, including the null. Our results confirm that daf-18/PTEN is important for promoting starvation resistance and developmental arrest and that it is a potent regulator of PI3K signaling, and they highlight challenges of using genetic analysis to link specific DAF-18/PTEN enzymatic activities to particular phenotypes.
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Affiliation(s)
- Jingxian Chen
- Department of Biology, Duke University, Durham, NC 27708, USA
| | - Linda Y Tang
- Department of Biology, Duke University, Durham, NC 27708, USA
| | - Maya E Powell
- Department of Biology, Duke University, Durham, NC 27708, USA
| | - James M Jordan
- Department of Biology, Duke University, Durham, NC 27708, USA
| | - L Ryan Baugh
- Department of Biology, Duke University, Durham, NC 27708, USA
- Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA
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Skolariki A, D’Costa J, Little M, Lord S. Role of PI3K/Akt/mTOR pathway in mediating endocrine resistance: concept to clinic. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:172-199. [PMID: 36046843 PMCID: PMC9400772 DOI: 10.37349/etat.2022.00078] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 02/11/2022] [Indexed: 01/06/2023] Open
Abstract
The majority of breast cancers express the estrogen receptor (ER) and for this group of patients, endocrine therapy is the cornerstone of systemic treatment. However, drug resistance is common and a focus for breast cancer preclinical and clinical research. Over the past 2 decades, the PI3K/Akt/mTOR axis has emerged as an important driver of treatment failure, and inhibitors of mTOR and PI3K are now licensed for the treatment of women with advanced ER-positive breast cancer who have relapsed on first-line hormonal therapy. This review presents the preclinical and clinical data that led to this new treatment paradigm and discusses future directions.
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Affiliation(s)
- Aglaia Skolariki
- Department of Oncology, University of Oxford, Churchill Hospital, OX3 7LE Oxford, UK
| | - Jamie D’Costa
- Department of Oncology, University of Oxford, Churchill Hospital, OX3 7LE Oxford, UK
| | - Martin Little
- Department of Oncology, Churchill Hospital, OX3 7LE Oxford, UK
| | - Simon Lord
- Department of Oncology, University of Oxford, Churchill Hospital, OX3 7LE Oxford, UK
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Dawsey SJ, Gupta S. Hereditary Renal Cell Carcinoma. KIDNEY CANCER 2022. [DOI: 10.3233/kca-210008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND: Hereditary renal cell carcinoma (RCC) is a complex and rapidly evolving topic as there is a growing body of literature regarding inherited syndromes and mutations associated with an increased risk of RCC. OBJECTIVES: We sought to systematically review 13 hereditary syndromes associated with RCC; von Hippel-Lindau Disease associated RCC (VHLRCC), BAP-1 associated clear cell RCC (BAPccRCC), Familial non-von Hippel Lindau clear cell RCC (FccRCC), Tuberous Sclerosis Complex associated RCC (TSCRCC), Birt-Hogg-Dub e ´ Syndrome associated RCC (BHDRCC), PTEN Hamartoma Tumor Syndrome associated RCC (PHTSRCC), Microphthalmia-associated Transcription Family translocation RCC (MiTFtRCC), RCC with Chromosome 6p Amplification (TFEBRCC), Autosomal Dominant Polycystic Kidney Disease Associated RCC (ADPKDRCC), Hereditary Leiomyomatosis associated RCC (HLRCC), Succinate Dehydrogenase RCC (SDHRCC), Hereditary Papillary RCC (HPRCC), and ALK-Rearrangement RCC (ALKRCC). RESULTS: Hereditary RCC is generally associated with early age of onset, multifocal and/or bilateral lesions, and aggressive disease course. VHLRCC, BAPccRCC, FccRCC, and certain mutations resulting in SDHRCC are associated with clear cell RCC (ccRCC). HPRCC is associated with Type 1 papillary RCC. HLRCC is associated with type 2 papillary RCC. BHDRCC is associated with Chromophobe RCC. TSCRCC, PHTSRCC, MiTFtRCC, TFEBRCC, ADPKDRCC, certain SDHRCC and ALKRCC have variable histology. CONCLUSIONS: There has been tremendous advancement in our understanding of the pathophysiology of hereditary RCC. Ongoing research will refine our understanding of hereditary RCC and its therapeutic targets.
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Affiliation(s)
- Scott J. Dawsey
- Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Shilpa Gupta
- Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
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Zhang X, Wang L, Huang N, Zheng Y, Cai L, Ke Q, Wu S. MicroRNA-455-3p regulates proliferation and osteoclast differentiation of RAW264.7 cells by targeting PTEN. BMC Musculoskelet Disord 2022; 23:340. [PMID: 35397519 PMCID: PMC8994399 DOI: 10.1186/s12891-022-05266-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 03/24/2022] [Indexed: 11/25/2022] Open
Abstract
Background Macrophages are one of the important cells in immune system. In this article, we aim to explore the regulatory role of miR-455-3p on proliferation and osteoblast differentiation of RAW264.7 cells. Methods Expression levels of genes and proteins in cells were tested via qRT-PCR and western blot. The targeted correlation between miR-455-3p and PTEN was identified by luciferase analysis. MTT assay and flow cytometry were applied to detect the proliferation and apoptosis of cells. Osteoclastogenesis was completed by stimulating RAW 264.7 cells with RANKL. Tartrate-resistant acid phosphatase (TRAP) activity in different groups of cells were assessed. Results Firstly, we determined that up-regulation of miR-455-3p promoted the proliferation and inhibited apoptosis of RAW 264.7 cells. MiR-455-3p deficiency played opposite effect in RAW 264.7 cells. Additionally, osteoclastogenesis-related factors (TRAP, CTSK and NFATc1) expression levels were remarkably up-regulated in miR-455-3p-mimic group of RAW264.7 cells treated with RANKL, but decreased in inhibitor group. Luciferase assay proved that miR-455-3p targeted PTEN. We took a further step and found overexpression of PTEN significantly inhibited the increased proliferation and osteoblast differentiation of RAW264.7 cells induced by miR-455-3p. Conclusions Our findings supported basic to explore the molecular mechanism of proliferation and osteoblast differentiation of RAW264.7 cells. Supplementary Information The online version contains supplementary material available at 10.1186/s12891-022-05266-0.
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Fumarate inhibits PTEN to promote tumorigenesis and therapeutic resistance of type2 papillary renal cell carcinoma. Mol Cell 2022; 82:1249-1260.e7. [PMID: 35216667 DOI: 10.1016/j.molcel.2022.01.029] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 12/10/2021] [Accepted: 01/28/2022] [Indexed: 12/22/2022]
Abstract
Fumarate is an oncometabolite. However, the mechanism underlying fumarate-exerted tumorigenesis remains unclear. Here, utilizing human type2 papillary renal cell carcinoma (PRCC2) as a model, we show that fumarate accumulates in cells deficient in fumarate hydratase (FH) and inhibits PTEN to activate PI3K/AKT signaling. Mechanistically, fumarate directly reacts with PTEN at cysteine 211 (C211) to form S-(2-succino)-cysteine. Succinated C211 occludes tethering of PTEN with the cellular membrane, thereby diminishing its inhibitory effect on the PI3K/AKT pathway. Functionally, re-expressing wild-type FH or PTEN C211S phenocopies an AKT inhibitor in suppressing tumor growth and sensitizing PRCC2 to sunitinib. Analysis of clinical specimens indicates that PTEN C211 succination levels are positively correlated with AKT activation in PRCC2. Collectively, these findings elucidate a non-metabolic, oncogenic role of fumarate in PRCC2 via direct post-translational modification of PTEN and further reveal potential stratification strategies for patients with FH loss by combinatorial AKTi and sunitinib therapy.
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