Carbonic Anhydrase IX Interacts with Bicarbonate Transporters in Lamellipodia and Increases Cell Migration via Its Catalytic Domain

Švastová, Eliška; Witarski, Wojciech; Csáderová, Lucia; Košík, Ivan; Škvarková, Lucia; Hulı́ková, Alžbeta; Zaťovičová, Miriam; Baráthová, Monika; Kopáček, Juraj; Pastorek, Jaromı́r; Pastoreková, Silvia

doi:10.1074/jbc.m111.286062

Cited by 165 publications

(209 citation statements)

References 38 publications

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“…This was further validated by our experiment in which supplementation with bicarbonate rescued the heterozygous mutant parasites from growth defects and intracellular acidosis in low pH medium. Physical and functional interaction of the Na + /HCO 3 − cotransporter or Cl − /HCO 3 − anion exchanger with transmembrane carbonic anhydrase 9 has been shown to control cytosolic pH in cancer cells and cardiomyocytes (Ditte et al, 2011;Svastova et al, 2012;Swietach et al, 2007;Orlowski et al, 2012). It will be fascinating to verify if such a carbonic anhydrasebicarbonate transport metabolon is operational in Leishmania parasites.…”

Section: Discussionmentioning

confidence: 99%

Interplay between a cytosolic and a cell surface carbonic anhydrase in pH homeostasis and acid tolerance of Leishmania

Pal

Abbasi

Mondal

et al. 2017

Journal of Cell Science

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Leishmania parasites have evolved to endure the acidic phagolysosomal environment within host macrophages. How Leishmania cells maintain near-neutral intracellular pH and proliferate in such a proton-rich mileu remains poorly understood. We report here that, in order to thrive in acidic conditions, Leishmania major relies on a cytosolic and a cell surface carbonic anhydrase, LmCA1 and LmCA2, respectively. Upon exposure to acidic medium, the intracellular pH of the LmCA1 +/− , LmCA2 +/− and LmCA1 +/− :LmCA2 +/− mutant strains dropped by varying extents that led to cell cycle delay, growth retardation and morphological abnormalities. Intracellular acidosis and growth defects of the mutant strains could be reverted by genetic complementation or supplementation with bicarbonate. When J774A.1 macrophages were infected with the mutant strains, they exhibited much lower intracellular parasite burdens than their wild-type counterparts. However, these differences in intracellular parasite burden between the wild-type and mutant strains were abrogated if, before infection, the macrophages were treated with chloroquine to alkalize their phagolysosomes. Taken together, our results demonstrate that haploinsufficiency of LmCA1 and/or LmCA2 renders the parasite acid-susceptible, thereby unravelling a carbonic anhydrase-mediated pH homeostatic circuit in Leishmania cells.

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Section: Discussionmentioning

confidence: 99%

Interplay between a cytosolic and a cell surface carbonic anhydrase in pH homeostasis and acid tolerance of Leishmania

Pal

Abbasi

Mondal

et al. 2017

Journal of Cell Science

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“…CA9 is a cancer-associated transmembrane enzyme, involving in pH regulation and ion transport 89 . The CA9 expression is driven by hypoxia 90 , and it is overexpressed preferentially at the edge of the tumor 90 while other did observe it at the core of tumor (necrotic region) 91 . CA9 is correlated with tumor cell invasion/migration 90,92 ; it is associated with poor prognosis of the tumor 93,94 .…”

Section: Carbonic Anhydrases 9 (Caix)mentioning

confidence: 99%

“…The CA9 expression is driven by hypoxia 90 , and it is overexpressed preferentially at the edge of the tumor 90 while other did observe it at the core of tumor (necrotic region) 91 . CA9 is correlated with tumor cell invasion/migration 90,92 ; it is associated with poor prognosis of the tumor 93,94 . Also, CA9 is associated with resistance to chemotherapy [95][96][97][98][99] .…”

Section: Carbonic Anhydrases 9 (Caix)mentioning

confidence: 99%

Tumor metabolism, cancer cell transporters, and microenvironmental resistance

Alfarouk

2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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Cancer cells reprogram their metabolic machineries to enter into permanent glycolytic pathways. The full reason for such reprogramming takes place is unclear. However, this metabolic switch is not made in vain for the lactate that is generated and exported outside cells is reused by other cells. This results in the generation of a pH gradient between the low extracellular pH that is acidic (pHe) and the higher cytosolic alkaline or near neutral pH (pHi) environments that are tightly regulated by the overexpression of several pumps and ion channels (e.g. NHE-1, MCT-1, V-ATPase, CA9, and CA12). The generation of this unique pH gradient serves as a determining factor in defining ''tumor fitness''. Tumor fitness is the capacity of the tumor to invade and metastasize due to its ability to reduce the efficiency of the immune system and confer resistance to chemotherapy. In this article, we highlight the importance of tumor microenvironment in mediating the failure of chemotherapeutic agents.

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“…This re sults from the ab nor mal meta bolic ac tiv ity of can cer cells, in clud ing in creased gly colytic flux and lac tic acid re lease [150]; car bon diox ide pro duc tion by the TCA cy cle and the pen tose phos phate path way (PPP) [151][152][153][154]; over ex pres sion or up reg u lated ac tiv ity of car bonic an hy drases [155,156] and pro ton trans porters [156]; and de creased pro ton clear ance in the tu mor en vi ron ment [157]. Pro ton ex tru sion and ex tra cel lu lar acid i fi ca tion make ad her ent junc tions lose [158], stim u late mi gra tion and cy toskele ton re or ga ni za tion [159][160][161][162][163], and pro mote the ex pres sion [164,165], re lease [166,167] and ac tiv ity [167,168] of pro teases that de grade the ex tra cel lu lar ma trix. Hence, acidic prim ing was shown to be suf fi cient to in crease lung col o niza tion fol low ing sar coma and melanoma tu mor cell in jec tion in the tail vein of mice [163,167,169,170].…”

Section: Metabolic Contribution To Cancer Metastasismentioning

confidence: 99%

Cancer metabolism in space and time: Beyond the Warburg effect

Danhier

Bański

Payen

et al. 2017

Biochimica et Biophysica Acta (BBA) - Bioenergetics

177

139

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Available online xxx Keywords:Can cer Me tab o lism Mi to chon dria Het ero gene ity Metas ta sis A B S T R A C T Al tered me tab o lism in can cer cells is piv otal for tu mor growth, most no tably by pro vid ing en ergy, re duc ing equiv a lents and build ing blocks while sev eral metabo lites ex ert a sig nal ing func tion pro mot ing tu mor growth and pro gres sion. A can cer tis sue can not be sim ply re duced to a bulk of pro lif er at ing cells. Tu mors are in deed com plex and dy namic struc tures where sin gle cells can het ero ge neously per form var i ous bi o log i cal ac tiv i ties with dif fer ent meta bolic re quire ments. Be cause tu mors are com posed of dif fer ent types of cells with meta bolic ac tiv i ties af fected by dif fer ent spa tial and tem po ral con texts, it is im por tant to ad dress me tab o lism tak ing into ac count cel lu lar and bi o log i cal het ero gene ity. In this re view, we de scribe this het ero gene ity also in meta bolic fluxes, thus show ing the rel a tive con tri bu tion of dif fer ent meta bolic ac tiv i ties to tu mor pro gres sion ac cord ing to the cel lu lar con text. This ar ti cle is part of a Spe cial Is sue en ti tled Res pi ra tory com plex I, edited by Giuseppe Gas parre, Ro drigue Rossig nol and Pierre Son veaux. Abbreviations: ACL, ATP cit rate lyase; AMPK, adeno sine monophos phate ki nase; ARG1, L argi nine me tab o liz ing en zyme arginase 1; BCAA, branched chain amino acid; Bcl2, B cell lym phoma 2; CAF, can cer as so ci ated fi brob last; CIC, can cer ini ti at ing cell; COX2, cy tochrome ox i dase; CSC, can cer stem cell; CREB, cyclic adeno sine monophos phate re sponse el e ment bind ing pro tein; DEC1, dif fer en tially ex pressed in chon dro cytes 1; EMT, ep ithe lial to mes enchy mal tran si tion; FAK, fo cal ad he sion ki nase; FAS, fatty acid syn thase; FBP, fruc tose 1,6 bis pho s phate; FDG PET, [ F] flu o rodeoxyglu cose positron emis sion to mog ra phy; GAPDH, glyc er alde hyde 3 phos phate de hy dro ge nase; HIF 1, hy poxia ac ti vated fac tor 1; HK2, hex ok i nase 2; HMGB1, high mo bil ity group box 1; HU VEC, hu man um bil i cal vein en dothe lial cell; IFN γ, in ter feron gamma; LDH, lac tate de hy dro ge nase; MEF, murine em bry onic fi brob last; MET, mes enchy mal to ep ithe lial tran si tion; MRI, mag netic res o nance imag ing; mTORC1, mam malian tar get of ra pamycin com plex 1; NSCLC, non small cell lung can cer; OX PHOS, ox ida tive phos pho ry la tion; PDAC, pan cre atic duc tal ade no car ci noma; PHD, pro lyl hy drox y lase; pHe, ex tra cel lu lar pH; pHi, in tra cel lu lar pH; PK, pyru vate ki nase; PPP, pen tose phos phate path way; REDD1, reg u lated in de vel op ment and DNA dam age re sponse 1; RhoA, Ras ho molog gene fam ily, mem ber A; ROS, re ac tive oxy gen species; SASP, senes cence as so ci ated se cre tory phe no type; SCO2, syn the sis of cy tochrome ox i dase 2; SGK 1, serum and glu co cor ti coid reg u lated ki nase 1 Sirt1, sir tuin 1; TAM, tu mor as so ci ated macrophage; TIGAR, TP53 in duced gly col y ...

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Carbonic Anhydrase IX Interacts with Bicarbonate Transporters in Lamellipodia and Increases Cell Migration via Its Catalytic Domain

Cited by 165 publications

References 38 publications

Interplay between a cytosolic and a cell surface carbonic anhydrase in pH homeostasis and acid tolerance of Leishmania

Interplay between a cytosolic and a cell surface carbonic anhydrase in pH homeostasis and acid tolerance of Leishmania

Tumor metabolism, cancer cell transporters, and microenvironmental resistance

Cancer metabolism in space and time: Beyond the Warburg effect

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