TITLE

Knock-down of hypoxia-induced carbonic anhydrases IX and XII radiosensitizes tumor cells by increasing intracellular acidosis

AUTHOR(S)
Doyen, Jérome; Parks, Scott K.; Marcié, Serge; Pouysségur, Jacques; Chiche, Johanna
PUB. DATE
January 2013
SOURCE
Frontiers in Oncology;Jan2013, Vol. 3, p1
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
The relationship between acidosis with in the tumor microenvironment and radioresistance of hypoxic tumor cells remains unclear. Previously we reported that hypoxia-induced carbonic anhydrases (CA) IX and CAXII constitute a robust intracellular pH (pHi)-regulating system that confers a survival advantage on hypoxic human colon carcinoma LS174Tr cells in acidic microenvironments. Here we investigate the role of acidosis, CAIX and CAXII knock-down in combination with ionizing radiation. Fibroblasts cells (-/+ CAIX) and LS174Tr cells (inducible knock-down for ca9/ca12) were analyzed for cell cycle phase distribution and survival after irradiation in extracellular pHo manipulations and hypoxia (1% O2) exposure. Radiotherapy was used to target ca9/ca12-silenced LS174Tr tumors grown in nude mice. We found that diminishing the pHi-regulating capacity of fibroblasts through inhibition of Na+/H+ exchanger 1 sensitize cells to radiation-induced cell death. Secondly, the pHiregulating function of CAIX plays a key protective role in irradiated fibroblasts in an acidic environment as accompanied by a reduced number of cells in the radiosensitive phases of the cell cycle. Thirdly, we demonstrate that irradiation of LS174Tr spheroids, silenced for either ca9 or both ca9/ca12, showed a respective 50 and 75% increase in cell death as a result of a decrease in cell number in the radioresistant S phase and a disruption of CA-mediated pHi regulation. Finally, LS174Tr tumor progression was strongly decreased when ca9/ca12 silencing was combined with irradiation in vivo. These findings highlight the combinatory use of radiotherapy with targeting of the pHi-regulating CAs as an anti-cancer strategy.
ACCESSION #
88067124

 

Related Articles

  • Relationship between tumor radioresistance induced by intermittent hypoxia and cell cycle control. Nakamura, Yoshinari // Japanese Journal of Veterinary Research;May2013, Vol. 61 Issue 1/2, p67 

    The article focuses on a study that investigates the occurrence of intermittent-hypoxia-induced radioresistance across multiple cell lines and also reflects on the effect of intermittent hypoxia on the radiation sensitivities. The study reveals the occurrence of tumor radio resistance caused by...

  • Knock-down of hypoxia-induced carbonic anhydrases IX and XII radiosensitizes tumor cells by increasing intracellular acidosis. Doyen, Jérôme; Parks, Scott Kenneth; Marcié, Serge; Pouysségur, Jacques; Chiche, Johanna // Frontiers in Oncology;Dec2012, Vol. 2, p1 

    The relationship between acidosis within the tumor microenvironment and radioresistance of hypoxic tumor cells remains unclear. Previously we reported that hypoxia-induced carbonic anhydrases CAIX and CAXII constitute a robust pHi-regulating system that confers a survival advantage on hypoxic...

  • Short-term treatment with a novel HIF-prolyl hydroxylase inhibitor (GSK1278863) failed to improve measures of performance in subjects with claudication-limited peripheral artery disease. Olson, Eric; Demopoulos, Laura; Haws, Thomas F; Hu, Erding; Fang, Zixing; Mahar, Kelly M; Qin, Pu; Lepore, John; Bauer, Timothy A; Hiatt, William R // Vascular Medicine;Dec2014, Vol. 19 Issue 6, p473 

    Hypoxia inducible factor (HIF) stabilization by HIF-prolyl hydroxylase (PHD) inhibitors may improve ischemic conditions such as peripheral artery disease (PAD). This multicenter, randomized, placebo-controlled study evaluated the safety and efficacy of GSK1278863 (an oral PHD inhibitor) in...

  • Identification of a hypoxia-regulated miRNA signature in bladder cancer and a role for miR-145 in hypoxia-dependent apoptosis. Blick, C; Ramachandran, A; McCormick, R; Wigfield, S; Cranston, D; Catto, J; Harris, A L // British Journal of Cancer;8/11/2015, Vol. 113 Issue 4, p634 

    Background:Hypoxia leads to the stabilisation of the hypoxia-inducible factor (HIF) transcription factor that drives the expression of target genes including microRNAs (miRNAs). MicroRNAs are known to regulate many genes involved in tumourigenesis. The aim of this study was to identify...

  • Adipose differentiation-related protein is not involved in hypoxia inducible factor-1-induced lipid accumulation under hypoxia. GUOMIN SHEN; NING NING; XINGSHENG ZHAO; XI LIU; GUANGYU WANG; TIANZHEN WANG; RAN ZHAO; CHAO YANG; DONGMEI WANG; PINGYUAN GONG; YAN SHEN; YONGJIAN SUN; XIAO ZHAO; YINJI JIN; WEIWEI YANG; YAN HE; LEI ZHANG; XIAOMING JIN; XIAOBO LI // Molecular Medicine Reports;2015, Vol. 12 Issue 6, p8055 

    Increasing evidence has showed that hypoxia inducible factor-1 (HIF1) has an important role in hypoxia-induced lipid accumulation, a common feature of solid tumors; however, its role remains to be fully elucidated. Adipose differentiation-related protein (ADRP), a structural protein of lipid...

  • DIAMETER RED BLOOD CELLS OF HUMAN IN ACUTE NORMOBARIC HYPOXIA. N. P., Mongalev; L. I., Irzhak; N. N., Potolizina // In the World of Scientific Discoveries / V Mire Nauchnykh Otkryt;2014, Vol. 50 Issue 1, p230 

    In healthy adult men erythrocyte diameter distribution in venous blood (Price-Jones curve) changes synchronously with the changes of blood pH (H+). Before and after hypoxic exposure the distribution curve has one peak, and erythrocyte diameter and pH fall into the normal intervals. At the 10th...

  • Hypoxia-inducible factor 1-α in chronic gastrointestinal ischemia. Harki, Jihan; Sana, Aria; Noord, Désirée; Diest, Paul; Groep, Petra; Kuipers, Ernst; Moons, Leon; Biermann, Katharina; Tjwa, Eric // Virchows Archiv;Feb2015, Vol. 466 Issue 2, p125 

    Chronic gastrointestinal ischemia (CGI) is the result of decreased mucosal perfusion. Typical histological characteristics are lacking which hamper its early diagnosis. Hypoxia-inducible factor-1α (HIF-1α) is expressed under acute hypoxia. We investigated HIF-1α expression in chronic...

  • Pharmacologic Activation of Tumor Hypoxia: A Means to Increase Tumor 2-Deoxy-2-[18F]Fluoro-D-Glucose Uptake? Mees, Gilles; Dierckx, Rudi; Vangestel, Christel; Laukens, Debby; Van Damme, Nancy; de Wiele, Christophe Van // Molecular Imaging;Jan/Feb2013, Vol. 12 Issue 1, p49 

    Tumor hypoxia and tumor metabolism are linked through the activation of metabolic genes following hypoxia-inducible factor 1 (HIF- 1) activation. This raises the question of whether this relationship can be exploited to improve 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography...

  • Antiangiogenic effects of ganetespib in colorectal cancer mediated through inhibition of HIF-1α and STAT-3. Ganji, Purnachandra; Park, Wungki; Wen, Jing; Mahaseth, Hemchandra; Landry, Jerome; Farris, Alton; Willingham, Field; Sullivan, Patrick; Proia, David; El-Hariry, Iman; Taliaferro-Smith, LaTonia; Diaz, Roberto; El-Rayes, Bassel // Angiogenesis;Oct2013, Vol. 16 Issue 4, p903 

    Hypoxia-inducible factors (HIFs) and STAT-3 play essential roles in angiogenesis. HIF-1α and STAT-3 are clients of the heat shock protein 90 (HSP90). We hypothesized that ganetespib, a potent HSP90 inhibitor, would disrupt angiogenesis in colorectal cancer (CRC) through inhibition of...

Share

Read the Article

Courtesy of VIRGINIA BEACH PUBLIC LIBRARY AND SYSTEM

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics