NBCn1 and NHE1 expression and activity in ΔNErbB2 receptor-expressing MCF-7 breast cancer cells: Contributions to pHi regulation and chemotherapy resistance

Lauritzen, Gitte; Jensen, Mie Birgitte Frid; Boedtkjer, Ebbe; Dybboe, Rie; Aalkjær, Christian; Nylandsted, Jesper; Pedersen, Stine Falsig

doi:10.1016/j.yexcr.2010.06.005

Cited by 110 publications

(148 citation statements)

References 50 publications

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“…18). Briefly, cells were grown in RPMI-1640 supplemented with 6% heat-inactivated FBS, 1% penicillin/streptomycin, 2 mg/mL tetracycline, 1 mg/mL puromycin, and 200 mg/mL G418 (hereafter Complete Medium, CM).…”

Section: Cell Lines and Culture Conditionsmentioning

confidence: 99%

“…Furthermore, these questions have, to our knowledge, not previously been addressed specifically for DNErbB2-expressing breast cancer. Notably, despite their increased motility and invasiveness, DNErbB2-expressing cells do not exhibit increased proliferation, but in fact can undergo senescence after long-term DNErbB2 expression (17); furthermore, neither full-length (16) nor truncated (18) ErbB2 confers resistance to cell death stimuli. We hypothesize that this reflects that both pro-and antiapoptotic and -proliferative pathways are upregulated by DNErbB2.…”

Section: Introductionmentioning

confidence: 99%

“…We hypothesize that this reflects that both pro-and antiapoptotic and -proliferative pathways are upregulated by DNErbB2. We recently showed that cisplatin induces caspase-and cathepsin-dependent pathways in DNErbB2-expressing MCF-7 breast cancer cells (18), yet upstream events induced by cisplatin, as well as possible roles of other death pathways, were not investigated. Furthermore, inhibition or knockdown of the Na þ /H þ exchanger NHE1 (SLC9A1) strongly sensitized DNErbB2-expressing cells to cisplatin-induced death (18).…”

Section: Introductionmentioning

confidence: 99%

“…We recently showed that cisplatin induces caspase-and cathepsin-dependent pathways in DNErbB2-expressing MCF-7 breast cancer cells (18), yet upstream events induced by cisplatin, as well as possible roles of other death pathways, were not investigated. Furthermore, inhibition or knockdown of the Na þ /H þ exchanger NHE1 (SLC9A1) strongly sensitized DNErbB2-expressing cells to cisplatin-induced death (18). This would imply a possible effect of cellular pH (pH i ) regulation; however, inhibition of the other major acid extruding transporter in these cells, the Na þ ,HCO 3 À cotransporter NBCn1 (SLC4A7), had no net effect on cell death, and in fact attenuated lysosomal membrane permeabilization (LMP) and cysteine cathepsin release (18).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, inhibition or knockdown of the Na þ /H þ exchanger NHE1 (SLC9A1) strongly sensitized DNErbB2-expressing cells to cisplatin-induced death (18). This would imply a possible effect of cellular pH (pH i ) regulation; however, inhibition of the other major acid extruding transporter in these cells, the Na þ ,HCO 3 À cotransporter NBCn1 (SLC4A7), had no net effect on cell death, and in fact attenuated lysosomal membrane permeabilization (LMP) and cysteine cathepsin release (18). This led us to hypothesize that the functional availability of the two transporters is differentially regulated by cisplatin.…”

Section: Introductionmentioning

confidence: 99%

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Constitutively Active ErbB2 Regulates Cisplatin-Induced Cell Death in Breast Cancer Cells via Pro- and Antiapoptotic Mechanisms

Sigurðsson

Olesen

Dybboe

et al. 2015

Molecular Cancer Research

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Despite the frequent expression of N-terminally truncated ErbB2 (DNErbB2/p95HER2) in breast cancer and its association with Herceptin resistance and poor prognosis, it remains poorly understood how DNErbB2 affects chemotherapy-induced cell death. Previously it was shown that DNErbB2 upregulates acid extrusion from MCF-7 breast cancer cells and that inhibition of the Na þ /H þ exchanger (SLC9A1/NHE1) strongly sensitizes DNErbB2-expressing MCF-7 cells to cisplatin chemotherapy. The aim of this study was to identify the mechanism through which DNErbB2 regulates cisplatin-induced breast cancer cell death, and determine how NHE1 regulates this process. Cisplatin treatment elicited apoptosis, ATM phosphorylation, upregulation of p53, Noxa (PMAIP1), and PUMA (BBC3), and cleavage of caspase-9, -7, fodrin, and PARP-1 in MCF-7 cells. Inducible DNErbB2 expression strongly reduced cisplatin-induced ATM-and p53-phosphorylation, augmented Noxa upregulation and caspase-9 and -7 cleavage, doubled p21 WAF1/Cip1 (CDKN1A) expression, and nearly abolished Bcl-2 expression. LC3-GFP analysis demonstrated that autophagic flux was reduced by cisplatin in a manner augmented by DNErbB2, yet did not contribute to cisplatin-induced death. Using knockdown approaches, it was shown that cisplatininduced caspase-7 cleavage in DNErbB2-MCF-7 cells was Noxaand caspase-9 dependent. This pathway was augmented by NHE1 inhibition, while the Na þ /HCO 3 À cotransporter (SLC4A7/ NBCn1) was internalized following cisplatin exposure.Implications: This work reveals that DNErbB2 strongly affects several major pro-and antiapoptotic pathways and provides mechanistic insight into the role of NHE1 in chemotherapy resistance. These findings have relevance for defining therapy regimens in breast cancers with DNErbB2 and/or NHE1 overexpression.

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Section: Cell Lines and Culture Conditionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Constitutively Active ErbB2 Regulates Cisplatin-Induced Cell Death in Breast Cancer Cells via Pro- and Antiapoptotic Mechanisms

Sigurðsson

Olesen

Dybboe

et al. 2015

Molecular Cancer Research

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Gram‐Scale Solution‐Phase Synthesis of Selective Sodium Bicarbonate Co‐transport Inhibitor S0859: in vitro Efficacy Studies in Breast Cancer Cells

Larsen¹,

Krogsgaard‐Larsen²,

Lauritzen³

et al. 2012

ChemMedChem

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Na(+)-coupled HCO(3)(-) transporters (NBCs) mediate the transport of bicarbonate ions across cell membranes and are thus ubiquitous regulators of intracellular pH. NBC dysregulation is associated with a range of diseases; for instance, NBCn1 is strongly up-regulated in a model of ErbB2-dependent breast cancer, a malignant and widespread cancer with no targeted treatment options, and single-nucleotide polymorphisms in NBCn1 genetically link to breast cancer development and hypertension. The N-cyanosulfonamide S0859 has been shown to selectively inhibit NBCs, and its availability on the gram scale is therefore of significant interest to the scientific community. Herein we describe a short and efficient synthesis of S0859 with an overall yield of 45 % from commercially available starting materials. The inhibitory effect of S0859 on recovery of intracellular pH after an acid load was verified in human and murine cancer cell lines in Ringer solutions. However, S0859 binds very strongly to components in plasma, and accordingly, measurements on isolated murine tissues showed no effect of S0859 at concentrations up to 50 μM.

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Role of Ion Transport in Control of Apoptotic Cell Death

Läng

Hoffmann

2012

Comprehensive Physiology

131

132

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Cell shrinkage is a hallmark and contributes to signaling of apoptosis. Apoptotic cell shrinkage requires ion transport across the cell membrane involving K + channels, Cl − or anion channels, Na + /H + exchange, Na + ,K + ,Cl − cotransport, and Na + /K + ATPase. Activation of K + channels fosters K + exit with decrease of cytosolic K + concentration, activation of anion channels triggers exit of Cl − , organic osmolytes, and HCO 3 − . Cellular loss of K + and organic osmolytes as well as cytosolic acidification favor apoptosis. Ca 2+ entry through Ca 2+ ‐permeable cation channels may result in apoptosis by affecting mitochondrial integrity, stimulating proteinases, inducing cell shrinkage due to activation of Ca 2+ ‐sensitive K + channels, and triggering cell‐membrane scrambling. Signaling involved in the modification of cell‐volume regulatory ion transport during apoptosis include mitogen‐activated kinases p38, JNK, ERK1/2, MEKK1, MKK4, the small G proteins Cdc42, and/or Rac and the transcription factor p53. Osmosensing involves integrin receptors, focal adhesion kinases, and tyrosine kinase receptors. Hyperosmotic shock leads to vesicular acidification followed by activation of acid sphingomyelinase, ceramide formation, release of reactive oxygen species, activation of the tyrosine kinase Yes with subsequent stimulation of CD95 trafficking to the cell membrane. Apoptosis is counteracted by mechanisms involved in regulatory volume increase (RVI), by organic osmolytes, by focal adhesion kinase, and by heat‐shock proteins. Clearly, our knowledge on the interplay between cell‐volume regulatory mechanisms and suicidal cell death is still far from complete and substantial additional experimental effort is needed to elucidate the role of cell‐volume regulatory mechanisms in suicidal cell death. © 2012 American Physiological Society. Compr Physiol 2:2037‐2061, 2012.

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NBCn1 and NHE1 expression and activity in ΔNErbB2 receptor-expressing MCF-7 breast cancer cells: Contributions to pHi regulation and chemotherapy resistance

Cited by 110 publications

References 50 publications

Constitutively Active ErbB2 Regulates Cisplatin-Induced Cell Death in Breast Cancer Cells via Pro- and Antiapoptotic Mechanisms

Constitutively Active ErbB2 Regulates Cisplatin-Induced Cell Death in Breast Cancer Cells via Pro- and Antiapoptotic Mechanisms

Gram‐Scale Solution‐Phase Synthesis of Selective Sodium Bicarbonate Co‐transport Inhibitor S0859: in vitro Efficacy Studies in Breast Cancer Cells

Role of Ion Transport in Control of Apoptotic Cell Death

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