Impairment of carbonic anhydrase IX ectodomain cleavage reinforces tumorigenic and metastatic phenotype of cancer cells

Kajanová, Ivana; Zaťovičová, Miriam; Jelenska, Lenka; Sedlakova, Olga; Baráthová, Monika; Csáderová, Lucia; Debreova, Michaela; Lukáčiková, Ľubomíra; Grossmannova, Katarina; Labudová, Martina; Golias, Tereza; Švastová, Eliška; Ludwig, Andreas; Müller, Petr; Vojtěšek, Bořivoj; Pastorek, Jaromı́r; Pastoreková, Silvia

doi:10.1038/s41416-020-0804-z

Cited by 15 publications

(24 citation statements)

References 62 publications

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“…The cells cotransfected with empty pSG5c plasmid and pSV2 neo were used as mock controls. C33a cell line constitutively expressing CAIX protein (C33a-CAIX) was prepared as described in [ 55 ].…”

Section: Methodsmentioning

confidence: 99%

PIMT Binding to C-Terminal Ala459 of CAIX Is Involved in Inside-Out Signaling Necessary for Its Catalytic Activity

Simko

Belvončíková

Csáderová

et al. 2020

IJMS

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Human carbonic anhydrase IX (CAIX), a unique member of the α carbonic anhydrase family, is a transmembrane glycoprotein with high enzymatic activity by which CAIX contributes to tumorigenesis through pH regulation. Due to its aberrant expression, CAIX is considered to be a marker of tumor hypoxia and a poor prognostic factor of several human cancers. Hypoxia-activated catalytic function of CAIX is dependent on posttranslational modification of its short intracellular domain. In this work, we have identified that C-terminal Ala459 residue, which is common across CAIX of various species as well as additional transmembrane isoforms, plays an important role in CAIX activation and in pH regulation. Moreover, structure prediction I-TASSER analysis revealed involvement of Ala459 in potential ligand binding. Using tandem mass spectrometry, Protein-L-isoaspartyl methyltransferase (PIMT) was identified as a novel interacting partner, further confirmed by an in vitro pulldown assay and an in situ proximity ligation assay. Indeed, suppression of PIMT led to increased alkalinization of culture media of C33a cells constitutively expressing CAIX in hypoxia. We suggest that binding of PIMT represents a novel intracellular signal required for enzymatic activity of CAIX with a potential unidentified downstream function.

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Section: Methodsmentioning

confidence: 99%

PIMT Binding to C-Terminal Ala459 of CAIX Is Involved in Inside-Out Signaling Necessary for Its Catalytic Activity

Simko

Belvončíková

Csáderová

et al. 2020

IJMS

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“…Interestingly, hypoxia-stabilized HIF-1α also promotes increased ADAM17 expression ( 117 ), which recognizes CAIX on the cell surface as a substrate and releases the enzymatically active ectodomain of CAIX ( 119 ). However, the consequences of this specific altered extracellular proteome for the exact pro- and anti-tumorigenic responses have yet to be investigated ( 120 ).…”

Section: Adam-induced Secretome In the Irradiated Tumor Microenvironmentmentioning

confidence: 99%

Combined Radiochemotherapy: Metalloproteinases Revisited

Waller

Pruschy

2021

Front. Oncol.

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Besides cytotoxic DNA damage irradiation of tumor cells triggers multiple intra- and intercellular signaling processes, that are part of a multilayered, treatment-induced stress response at the unicellular and tumor pathophysiological level. These processes are intertwined with intrinsic and acquired resistance mechanisms to the toxic effects of ionizing radiation and thereby co-determine the tumor response to radiotherapy. Proteolysis of structural elements and bioactive signaling moieties represents a major class of posttranslational modifications regulating intra- and intercellular communication. Plasma membrane-located and secreted metalloproteinases comprise a family of metal-, usually zinc-, dependent endopeptidases and sheddases with a broad variety of substrates including components of the extracellular matrix, cyto- and chemokines, growth and pro-angiogenic factors. Thereby, metalloproteinases play an important role in matrix remodeling and auto- and paracrine intercellular communication regulating tumor growth, angiogenesis, immune cell infiltration, tumor cell dissemination, and subsequently the response to cancer treatment. While metalloproteinases have long been identified as promising target structures for anti-cancer agents, previous pharmaceutical approaches mostly failed due to unwanted side effects related to the structural similarities among the multiple family members. Nevertheless, targeting of metalloproteinases still represents an interesting rationale alone and in combination with other treatment modalities. Here, we will give an overview on the role of metalloproteinases in the irradiated tumor microenvironment and discuss the therapeutic potential of using more specific metalloproteinase inhibitors in combination with radiotherapy.

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“…There is ample evidence showing the pro-tumoral activity of carbonic anhydrases, in particular the membrane CAs, 9 and 12 (CAIX and CAXII) [53][54][55][56][57][58][59], but also non-membrane CAIV [60], CAIII [61], and CAII.…”

Section: The Phtome and How The Paradigm Appearsmentioning

confidence: 99%

Targeting the pH Paradigm at the Bedside: A Practical Approach

Koltai¹

2020

IJMS

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The inversion of the pH gradient in malignant tumors, known as the pH paradigm, is increasingly becoming accepted by the scientific community as a hallmark of cancer. Accumulated evidence shows that this is not simply a metabolic consequence of a dysregulated behavior, but rather an essential process in the physiopathology of accelerated proliferation and invasion. From the over-simplification of increased lactate production as the cause of the paradigm, as initially proposed, basic science researchers have arrived at highly complex and far-reaching knowledge, that substantially modified that initial belief. These new developments show that the paradigm entails a different regulation of membrane transporters, electrolyte exchangers, cellular and membrane enzymes, water trafficking, specialized membrane structures, transcription factors, and metabolic changes that go far beyond fermentative glycolysis. This complex world of dysregulations is still shuttered behind the walls of experimental laboratories and has not yet reached bedside medicine. However, there are many known pharmaceuticals and nutraceuticals that are capable of targeting the pH paradigm. Most of these products are well known, have low toxicity, and are also inexpensive. They need to be repurposed, and this would entail shorter clinical studies and enormous cost savings if we compare them with the time and expense required for the development of a new molecule. Will targeting the pH paradigm solve the “cancer problem”? Absolutely not. However, reversing the pH inversion would strongly enhance standard treatments, rendering them more efficient, and in some cases permitting lower doses of toxic drugs. This article’s goal is to describe how to reverse the pH gradient inversion with existing drugs and nutraceuticals that can easily be used in bedside medicine, without adding toxicity to established treatments. It also aims at increasing awareness among practicing physicians that targeting the pH paradigm would be able to improve the results of standard therapies. Some clinical cases will be presented as well, showing how the pH gradient inversion can be treated at the bedside in a simple manner with repurposed drugs.

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Impairment of carbonic anhydrase IX ectodomain cleavage reinforces tumorigenic and metastatic phenotype of cancer cells

Cited by 15 publications

References 62 publications

PIMT Binding to C-Terminal Ala459 of CAIX Is Involved in Inside-Out Signaling Necessary for Its Catalytic Activity

PIMT Binding to C-Terminal Ala459 of CAIX Is Involved in Inside-Out Signaling Necessary for Its Catalytic Activity

Combined Radiochemotherapy: Metalloproteinases Revisited

Targeting the pH Paradigm at the Bedside: A Practical Approach

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