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Carbonic anhydrase inhibitor U-104 inhibits tumor progression through CA9 and CA12 in tongue squamous cell carcinoma

  • 1.

    Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China

  • 2.

    Core Facility Center for Life Sciences, School of Life Sciences, University of Science and Technology of China, Hefei 230026, China

Cite this:
https://doi.org/10.52396/JUST-2021-0063
  • Received Date: 05 March 2021
  • Rev Recd Date: 11 March 2021
  • Publish Date: 31 May 2021
    Abstract

  • Abstract

    U-104, an effective inhibitor of carbonic anhydrases (CAs), has been shown as a potential anti-tumor drug in several human cancer types.However, the downstream mechanisms of U-104 and its functions in tongue squamous cell carcinoma (TSCC) remain unclear. It is neither confirmed that whether the anti-tumor effects of U-104 are dependent on CA9 and CA12. In this work, we found differentially expressed genes (DEGs) and potential cellular processes regulated by U-104 through RNA sequencing. The cell death-related, cell proliferation, migration and response to drug cellular processes were among the top GO (gene ontology) processes, which were consistent with the observed biological effects upon U-104 treatment in TSCC15 cells. Furthermore, knockdown (KD) of CA9 or CA12 completely eliminated the U-104 effects on the cell migration, cell death, and the expression of critical DEGs. All together, our study suggests the regulatory mechanisms of U-104 at the transcriptome level and demonstrates the anti-tumor functions of U-104 dependent on CA9 and CA12 in TSCC. Our findings expand the current knowledge on the anti-tumor functions of U-104 and provide a potential therapeutic option for TSCC.

    Abstract

    U-104, an effective inhibitor of carbonic anhydrases (CAs), has been shown as a potential anti-tumor drug in several human cancer types.However, the downstream mechanisms of U-104 and its functions in tongue squamous cell carcinoma (TSCC) remain unclear. It is neither confirmed that whether the anti-tumor effects of U-104 are dependent on CA9 and CA12. In this work, we found differentially expressed genes (DEGs) and potential cellular processes regulated by U-104 through RNA sequencing. The cell death-related, cell proliferation, migration and response to drug cellular processes were among the top GO (gene ontology) processes, which were consistent with the observed biological effects upon U-104 treatment in TSCC15 cells. Furthermore, knockdown (KD) of CA9 or CA12 completely eliminated the U-104 effects on the cell migration, cell death, and the expression of critical DEGs. All together, our study suggests the regulatory mechanisms of U-104 at the transcriptome level and demonstrates the anti-tumor functions of U-104 dependent on CA9 and CA12 in TSCC. Our findings expand the current knowledge on the anti-tumor functions of U-104 and provide a potential therapeutic option for TSCC.
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    • References(34)
  • [1]
    Supuran C T. Carbonic anhydrases: Novel therapeutic applications for inhibitors and activators. Nature Reviews Drug Discovery, 2008, 7: 168-181.
    [2]
    Supuran C T. Carbonic Anhydrase inhibition and the management of hypoxic tumors. Metabolites, 2017, 7: 48; doi: 10.3390/metabo7030048.
    [3]
    Chiche J, Ilc K, Laferriere J, et al. Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Research, 2009, 69: 358-368.
    [4]
    Doyen J, Parks S K, Marcie S, et al. Knock-down of hypoxia-induced carbonic anhydrases IX and XII radiosensitizes tumor cells by increasing intracellular acidosis.Frontiers in Oncology, 2012, 2: 199.
    [5]
    Ahlskog J K J, Dumelin C E, Trussel S, et al. In vivo targeting of tumor-associated carbonic anhydrases using acetazolamide derivatives.Bioorganic & Medicinal Chemistry Letters, 2009, 19: 4851-4856.
    [6]
    Neri D, Supuran C T. Interfering with pH regulation in tumours as a therapeutic strategy. Nature Reviews Drug Discovery, 2011, 10: 767-777.
    [7]
    Supuran C T. Carbonic anhydrase inhibitors and their potential in a range of therapeutic areas. Expert Opinion on Therapeutic Patents, 2018, 28: 709-712.
    [8]
    Pacchiano F, Aggarwal M, Avvaru B S, et al. Selective hydrophobic pocket binding observed within the carbonic anhydrase II active site accommodate different 4-substituted-ureido-benzenesulfonamides and correlate to inhibitor potency.Chemical Communications, 2010, 46: 8371-8373.
    [9]
    Pacchiano F, Carta F, McDonald P C, et al. Ureido-substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis. Journal of Medicinal Chemistry, 2011, 54: 1896-1902.
    [10]
    McDonald P C, Chafe S C, Brown W S, et al. Regulation of pH bycarbonic anhydrase 9 mediates survival of pancreatic cancer cells with activated KRAS in response to hypoxia. Gastroenterology, 2019, 157: 823-837.
    [11]
    Andreucci E, Ruzzolini J, Peppicelli S, et al. The carbonic anhydrase IX inhibitorSLC-0111 sensitises cancer cells to conventional chemotherapy. Journal of Enzyme Inhibition and Medicinal Chemistry, 2019, 34: 117-123.
    [12]
    McDonald P C, Chia S, Bedard P L, et al. A Phase 1study of SLC-0111, a novel inhibitor of carbonic anhydrase IX, in patients with advanced solid tumors. American Journal of Clinical Oncology, 2020,43:484-490.
    [13]
    Nocentini A, Supuran C T. Carbonic anhydrase inhibitors as antitumor/antimetastatic agents: A patent review (2008-2018). Expert Opinion on Therapeutic Patents, 2018, 28: 729-740.
    [14]
    Lock F E, McDonald P C, Lou Y, et al. Targeting carbonic anhydrase IX depletes breast cancer stem cells within the hypoxic niche.Oncogene, 2013, 32: 5210-5219.
    [15]
    Boyd N H, Walker K, Fried J, et al. Addition of carbonic anhydrase 9 inhibitor SLC-0111 to temozolomide treatment delays glioblastoma growth in vivo.JCI Insight, 2017, 2: e92928.
    [16]
    Shetty S S, Kudpaje A, Jayaraj R, et al. Tongue cancer: A discrete oral cavity subsite.Oral Oncology, 2019, 99: 104348.
    [17]
    Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA: A Cancer Journal for Clinicians, 2018, 68: 394-424.
    [18]
    Salo T, Vered M, Bello I O, et al. Insights into the role of components of the tumor microenvironment in oral carcinoma call for new therapeutic approaches. Experimental Cell Research, 2014, 325: 58-64.
    [19]
    Omura K. Current status of oral cancer treatment strategies: Surgical treatments for oral squamous cell carcinoma. International Journal of Clinical Oncology, 2014, 19: 423-430.
    [20]
    Roh J L, Cho K J, Kwon G Y, et al. The prognostic value of hypoxia markers in T2-staged oral tongue cancer.Oral Oncology, 2009, 45: 63-68.
    [21]
    Zheng G, Zhou M, Ou X, et al. Identification of carbonic anhydrase 9 as a contributor to pingyangmycin-induced drug resistance in human tongue cancer cells.FEBS Journal, 2010, 277: 4506-4518.
    [22]
    Xu G, Fang Z, Clark L H, et al. Topiramate exhibits anti-tumorigenic and metastatic effects in ovarian cancer cells. American Journal of Translational Research, 2018, 10: 1663-1676.
    [23]
    Wang Y, Shi K R, Zhang L, et al. Significantly enhanced tumor cellular and lysosomal hydroxychloroquine delivery by smart liposomes for optimal autophagy inhibition and improved antitumor efficiency with liposomal doxorubicin.Autophagy, 2016, 12: 949-962.
    [24]
    Corbet C, Bastien E, Santiago de Jesus J P, et al. TGFbeta2-induced formation of lipid droplets supports acidosis-driven EMT and the metastatic spreading of cancer cells.Nature Communications, 2020, 11: 454.
    [25]
    Parks S K, Chiche J, Pouyssegur J. Disrupting proton dynamics and energy metabolism for cancer therapy. Nature Reviews Cancer, 2013, 13: 611-623.
    [26]
    Rapisarda V, Borghesan M, Miguela V, et al. Integrinbeta 3 regulates cellular senescence by activating the TGF-β pathway. Cell Reports, 2017, 18: 2480-2493.
    [27]
    Yeh H W, Lee S S, Chang C Y, et al. A new switch for TGFβ in cancer. Cancer Research, 2019, 79: 3797-3805.
    [28]
    Vandenabeele P, Galluzzi L, Vanden Berghe T, et al. Molecular mechanisms of necroptosis:An ordered cellular explosion. Nature Reviews Molecular Cell Biology, 2010, 11: 700-714.
    [29]
    Vereecke L, Beyaert R, van Loo G. The ubiquitin-editing enzyme A20 (TNFAIP3) is a central regulator of immunopathology. Trends in Immunology, 2009, 30: 383-391.
    [30]
    Swayampakula M, McDonald P C, Vallejo M, et al. The interactome of metabolic enzyme carbonic anhydrase IX reveals novel roles in tumor cell migration and invadopodia/MMP14-mediated invasion.Oncogene, 2017, 36: 6244-6261.
    [31]
    Debreova M, Csaderova L, Burikova M, et al. CAIXregulates invadopodia formation through both a pH-dependent mechanism and interplay with actin regulatory proteins. International Journal of Molecular Sciences, 2019, 20: 19.
    [32]
    Wang H C, Chan L P, Cho S F. Targeting the immune microenvironment in the treatment of head and neck squamous cell carcinoma. Frontiers in Oncology, 2019, 9: 1084.
    [33]
    Zheng G, Peng C, Jia X, et al. ZEB1 transcriptionally regulated carbonic anhydrase 9 mediates the chemoresistance of tongue cancer via maintaining intracellular pH.Molecular Cancer, 2015, 14: 84.
    [34]
    Chafe S C, McDonald P C, Saberi S, et al. Targeting hypoxia-induced carbonic anhydrase IX enhances immune-checkpoint blockade locally and systemically. Cancer Immunology Research, 2019, 7: 1064-1078.
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    [1]
    Supuran C T. Carbonic anhydrases: Novel therapeutic applications for inhibitors and activators. Nature Reviews Drug Discovery, 2008, 7: 168-181.
    [2]
    Supuran C T. Carbonic Anhydrase inhibition and the management of hypoxic tumors. Metabolites, 2017, 7: 48; doi: 10.3390/metabo7030048.
    [3]
    Chiche J, Ilc K, Laferriere J, et al. Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Research, 2009, 69: 358-368.
    [4]
    Doyen J, Parks S K, Marcie S, et al. Knock-down of hypoxia-induced carbonic anhydrases IX and XII radiosensitizes tumor cells by increasing intracellular acidosis.Frontiers in Oncology, 2012, 2: 199.
    [5]
    Ahlskog J K J, Dumelin C E, Trussel S, et al. In vivo targeting of tumor-associated carbonic anhydrases using acetazolamide derivatives.Bioorganic & Medicinal Chemistry Letters, 2009, 19: 4851-4856.
    [6]
    Neri D, Supuran C T. Interfering with pH regulation in tumours as a therapeutic strategy. Nature Reviews Drug Discovery, 2011, 10: 767-777.
    [7]
    Supuran C T. Carbonic anhydrase inhibitors and their potential in a range of therapeutic areas. Expert Opinion on Therapeutic Patents, 2018, 28: 709-712.
    [8]
    Pacchiano F, Aggarwal M, Avvaru B S, et al. Selective hydrophobic pocket binding observed within the carbonic anhydrase II active site accommodate different 4-substituted-ureido-benzenesulfonamides and correlate to inhibitor potency.Chemical Communications, 2010, 46: 8371-8373.
    [9]
    Pacchiano F, Carta F, McDonald P C, et al. Ureido-substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis. Journal of Medicinal Chemistry, 2011, 54: 1896-1902.
    [10]
    McDonald P C, Chafe S C, Brown W S, et al. Regulation of pH bycarbonic anhydrase 9 mediates survival of pancreatic cancer cells with activated KRAS in response to hypoxia. Gastroenterology, 2019, 157: 823-837.
    [11]
    Andreucci E, Ruzzolini J, Peppicelli S, et al. The carbonic anhydrase IX inhibitorSLC-0111 sensitises cancer cells to conventional chemotherapy. Journal of Enzyme Inhibition and Medicinal Chemistry, 2019, 34: 117-123.
    [12]
    McDonald P C, Chia S, Bedard P L, et al. A Phase 1study of SLC-0111, a novel inhibitor of carbonic anhydrase IX, in patients with advanced solid tumors. American Journal of Clinical Oncology, 2020,43:484-490.
    [13]
    Nocentini A, Supuran C T. Carbonic anhydrase inhibitors as antitumor/antimetastatic agents: A patent review (2008-2018). Expert Opinion on Therapeutic Patents, 2018, 28: 729-740.
    [14]
    Lock F E, McDonald P C, Lou Y, et al. Targeting carbonic anhydrase IX depletes breast cancer stem cells within the hypoxic niche.Oncogene, 2013, 32: 5210-5219.
    [15]
    Boyd N H, Walker K, Fried J, et al. Addition of carbonic anhydrase 9 inhibitor SLC-0111 to temozolomide treatment delays glioblastoma growth in vivo.JCI Insight, 2017, 2: e92928.
    [16]
    Shetty S S, Kudpaje A, Jayaraj R, et al. Tongue cancer: A discrete oral cavity subsite.Oral Oncology, 2019, 99: 104348.
    [17]
    Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA: A Cancer Journal for Clinicians, 2018, 68: 394-424.
    [18]
    Salo T, Vered M, Bello I O, et al. Insights into the role of components of the tumor microenvironment in oral carcinoma call for new therapeutic approaches. Experimental Cell Research, 2014, 325: 58-64.
    [19]
    Omura K. Current status of oral cancer treatment strategies: Surgical treatments for oral squamous cell carcinoma. International Journal of Clinical Oncology, 2014, 19: 423-430.
    [20]
    Roh J L, Cho K J, Kwon G Y, et al. The prognostic value of hypoxia markers in T2-staged oral tongue cancer.Oral Oncology, 2009, 45: 63-68.
    [21]
    Zheng G, Zhou M, Ou X, et al. Identification of carbonic anhydrase 9 as a contributor to pingyangmycin-induced drug resistance in human tongue cancer cells.FEBS Journal, 2010, 277: 4506-4518.
    [22]
    Xu G, Fang Z, Clark L H, et al. Topiramate exhibits anti-tumorigenic and metastatic effects in ovarian cancer cells. American Journal of Translational Research, 2018, 10: 1663-1676.
    [23]
    Wang Y, Shi K R, Zhang L, et al. Significantly enhanced tumor cellular and lysosomal hydroxychloroquine delivery by smart liposomes for optimal autophagy inhibition and improved antitumor efficiency with liposomal doxorubicin.Autophagy, 2016, 12: 949-962.
    [24]
    Corbet C, Bastien E, Santiago de Jesus J P, et al. TGFbeta2-induced formation of lipid droplets supports acidosis-driven EMT and the metastatic spreading of cancer cells.Nature Communications, 2020, 11: 454.
    [25]
    Parks S K, Chiche J, Pouyssegur J. Disrupting proton dynamics and energy metabolism for cancer therapy. Nature Reviews Cancer, 2013, 13: 611-623.
    [26]
    Rapisarda V, Borghesan M, Miguela V, et al. Integrinbeta 3 regulates cellular senescence by activating the TGF-β pathway. Cell Reports, 2017, 18: 2480-2493.
    [27]
    Yeh H W, Lee S S, Chang C Y, et al. A new switch for TGFβ in cancer. Cancer Research, 2019, 79: 3797-3805.
    [28]
    Vandenabeele P, Galluzzi L, Vanden Berghe T, et al. Molecular mechanisms of necroptosis:An ordered cellular explosion. Nature Reviews Molecular Cell Biology, 2010, 11: 700-714.
    [29]
    Vereecke L, Beyaert R, van Loo G. The ubiquitin-editing enzyme A20 (TNFAIP3) is a central regulator of immunopathology. Trends in Immunology, 2009, 30: 383-391.
    [30]
    Swayampakula M, McDonald P C, Vallejo M, et al. The interactome of metabolic enzyme carbonic anhydrase IX reveals novel roles in tumor cell migration and invadopodia/MMP14-mediated invasion.Oncogene, 2017, 36: 6244-6261.
    [31]
    Debreova M, Csaderova L, Burikova M, et al. CAIXregulates invadopodia formation through both a pH-dependent mechanism and interplay with actin regulatory proteins. International Journal of Molecular Sciences, 2019, 20: 19.
    [32]
    Wang H C, Chan L P, Cho S F. Targeting the immune microenvironment in the treatment of head and neck squamous cell carcinoma. Frontiers in Oncology, 2019, 9: 1084.
    [33]
    Zheng G, Peng C, Jia X, et al. ZEB1 transcriptionally regulated carbonic anhydrase 9 mediates the chemoresistance of tongue cancer via maintaining intracellular pH.Molecular Cancer, 2015, 14: 84.
    [34]
    Chafe S C, McDonald P C, Saberi S, et al. Targeting hypoxia-induced carbonic anhydrase IX enhances immune-checkpoint blockade locally and systemically. Cancer Immunology Research, 2019, 7: 1064-1078.
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