The Expression of Carbonic Anhydrases II, IX and XII in Brain Tumors

Haapasalo, Joonas; Nordfors, Kristiina; Haapasalo, Hannu; Parkkila, Seppo

doi:10.3390/cancers12071723

Cited by 36 publications

(24 citation statements)

References 95 publications

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“…The latter are found in the subcellular locations where CO 2 /HCO 3 – interconversion is required, from the site of production in the mitochondria (mitochondrial CA-VA and CA-VB), moving into the cytosol (CA-I, CA-II, CA-III, CA-VII, CA-XIII), then to the plasma membrane (CA-IV, CA-IX, CA-XII, CA-XIV) and finally extracellularly (CA-VI secreted in saliva ( Supuran, 2008 ; Zamanova et al, 2019 ; Mishra et al, 2020 ). As genetic manipulation and selective inhibitors ( Supuran et al, 1998 ; Ilies et al, 2003 ; Smaine et al, 2007 ; Supuran, 2008 ; Güzel et al, 2009 ; Winum et al, 2009 ; Alterio et al, 2012 ; Akocak et al, 2016 ; Angeli et al, 2020 ) have become more available, there has been an increase in studies to determine the cell-specific function of different CA isoforms ( Ghandour et al, 1992 ; Sly and Hu, 1995 ; Kida et al, 2006 ; Pan et al, 2006 , 2012 ; Imtaiyaz Hassan et al, 2013 ; Shah et al, 2013b ; Akocak and Ilies, 2014 ; Angeli et al, 2017 ; Waheed and Sly, 2017 ; Haapasalo et al, 2020 ; Mishra et al, 2020 ). One of the most ubiquitously expressed and catalytically active isoform is CA-II, having a turnover rate for CO 2 hydration approaching diffusion limit (K cat = 1.4 × 10 6 s –1 ).…”

Section: Carbonic Anhydrasesmentioning

confidence: 99%

Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer’s Disease and Stroke

Lemon

Canepa

Ilies

et al. 2021

Front. Aging Neurosci.

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The Neurovascular Unit (NVU) is an important multicellular structure of the central nervous system (CNS), which participates in the regulation of cerebral blood flow (CBF), delivery of oxygen and nutrients, immunological surveillance, clearance, barrier functions, and CNS homeostasis. Stroke and Alzheimer Disease (AD) are two pathologies with extensive NVU dysfunction. The cell types of the NVU change in both structure and function following an ischemic insult and during the development of AD pathology. Stroke and AD share common risk factors such as cardiovascular disease, and also share similarities at a molecular level. In both diseases, disruption of metabolic support, mitochondrial dysfunction, increase in oxidative stress, release of inflammatory signaling molecules, and blood brain barrier disruption result in NVU dysfunction, leading to cell death and neurodegeneration. Improved therapeutic strategies for both AD and stroke are needed. Carbonic anhydrases (CAs) are well-known targets for other diseases and are being recently investigated for their function in the development of cerebrovascular pathology. CAs catalyze the hydration of CO2 to produce bicarbonate and a proton. This reaction is important for pH homeostasis, overturn of cerebrospinal fluid, regulation of CBF, and other physiological functions. Humans express 15 CA isoforms with different distribution patterns. Recent studies provide evidence that CA inhibition is protective to NVU cells in vitro and in vivo, in models of stroke and AD pathology. CA inhibitors are FDA-approved for treatment of glaucoma, high-altitude sickness, and other indications. Most FDA-approved CA inhibitors are pan-CA inhibitors; however, specific CA isoforms are likely to modulate the NVU function. This review will summarize the literature regarding the use of pan-CA and specific CA inhibitors along with genetic manipulation of specific CA isoforms in stroke and AD models, to bring light into the functions of CAs in the NVU. Although pan-CA inhibitors are protective and safe, we hypothesize that targeting specific CA isoforms will increase the efficacy of CA inhibition and reduce side effects. More studies to further determine specific CA isoforms functions and changes in disease states are essential to the development of novel therapies for cerebrovascular pathology, occurring in both stroke and AD.

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Section: Carbonic Anhydrasesmentioning

confidence: 99%

Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer’s Disease and Stroke

Lemon

Canepa

Ilies

et al. 2021

Front. Aging Neurosci.

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“…[ 16 ]. Eight different classes have been described but only α-CAs isoforms have been characterized in humans [ 17 ]. Many roles have been attributed to CAs, from intra- and extracellular pH regulation, to homeostasis maintenance and cell survival and migration [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Melanoma Cell Migration and Invasion Targeting the Hypoxic Tumor Associated CAXII

Giuntini

Monaci

Cau

et al. 2020

Cancers

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Background: Intratumoral hypoxia contributes to cancer progression and poor prognosis. Carbonic anhydrases IX (CAIX) and XII (CAXII) play pivotal roles in tumor cell adaptation and survival, as aberrant Hedgehog (Hh) pathway does. In malignant melanoma both features have been investigated for years, but they have not been correlated before and/or identified as a potential pharmacological target. Here, for the first time, we demonstrated that malignant melanoma cell motility was impaired by targeting CAXII via either CAs inhibitors or through the inhibition of the Hh pathway. Methods: We tested cell motility in three melanoma cell lines (WM-35, SK-MEL28, and A375), with different invasiveness capabilities. To this end we performed a scratch assay in the presence of the smoothened (SMO) antagonist cyclopamine (cyclo) or CAs inhibitors under normoxia or hypoxia. Then, we analyzed the invasiveness potential in the cell lines which were more affected by cyclo and CAs inhibitors (SK-MEL28 and A375). Western blot was employed to assess the expression of the hypoxia inducible factor 1α, CAXII, and FAK phosphorylation. Immunofluorescence staining was performed to verify the blockade of CAXII expression. Results: Hh inhibition reduced melanoma cell migration and CAXII expression under both normoxic and hypoxic conditions. Interestingly, basal CAXII expression was higher in the two more aggressive melanoma cell lines. Finally, a direct CAXII blockade impaired melanoma cell migration and invasion under hypoxia. This was associated with a decrease of FAK phosphorylation and metalloprotease activities. Conclusions: CAXII may be used as a target for melanoma treatment not only through its direct inhibition, but also through Hh blockade.

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“…CA2 is a member of a greater family of Carbonic Anhydrases which are highly conserved proteins in animals and plants [ 14 , 15 , 16 ]. Carbonic Anhydrases constitute a family of structurally divergent proton exchange proteins and particularly CA9 and CA12 have been previously described in GBM and other tumor entities as tumor cell-intrinsic carbonic anhydrases [ 17 , 18 ] and a current clinical trial uses acetazolamide in conjunction with TMZ (trial number NCT03011671) in GBM patients. CA9 has been identified as a hypoxia-dependent gene that is particularly relevant for the stem cell niche, in which GSCs can survive tumor-targeted therapies [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Carbonic Anhydrase 2 Overcomes Temozolomide Resistance in Glioblastoma Cells

Zhao

Schäfer

Zhang

et al. 2021

IJMS

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About 95% of Glioblastoma (GBM) patients experience tumor relapse as a consequence of resistance to the first-line standard chemotherapy using temozolomide (TMZ). Recent studies reported consistently elevated expression levels of carbonic anhydrase CA2 in recurrent glioblastoma and temozolomide-resistant glioblastoma stem-like cells (GSCs). Here we show that CA2 is preferentially expressed in GSCs and upregulated by TMZ treatment. When expressed in GBM cell lines, CA2 exerts significant metabolic changes reflected by enhanced oxygen consumption and increased extracellular acidification causing higher rates of cell invasion. Notably, GBM cells expressing CA2 respond to combined treatment with TMZ and brinzolamide (BRZ), a non-toxic and potent CA2 inhibitor. Interestingly, brinzolamide was more effective than the pan-CA inhibitor Acetazolamide (ACZ) to sensitize naïve GSCs and TMZ-resistant GSCs to TMZ induced cell death. Mechanistically, we demonstrated that the combined treatment of GBM stem cells with TMZ and BRZ caused autophagy of GBM cell lines and GSCs, reflected by enhanced LC3 cleavage (LC3-II) and p62 reduction. Our findings illustrate the potential of CA2 as a chemo-sensitizing drug target in recurrent GBM and propose a combined treatment of TMZ with CA2 inhibitor to tackle GBM chemoresistance and recurrence.

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The Expression of Carbonic Anhydrases II, IX and XII in Brain Tumors

Cited by 36 publications

References 95 publications

Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer’s Disease and Stroke

Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer’s Disease and Stroke

Inhibition of Melanoma Cell Migration and Invasion Targeting the Hypoxic Tumor Associated CAXII

Inhibition of Carbonic Anhydrase 2 Overcomes Temozolomide Resistance in Glioblastoma Cells

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