The Na+/H+ exchanger (NHE1) is an essntial component of the EGFR pathway in pancreatic ductual adenocarcinoma (PDAC) and is a new target for combination therapy
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1
University of Bari, Italy
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2
University Hospital Schleswig-Holstein Campus, Germany
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3
Max-Planck-Institute of Experimental Medicine, Germany
Background and aim. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers due to the lack of clinical symptoms in its early stages and aggressive invasive growth and rapid metastasis combined with a strong desmoplastic reaction with deep hypoxia that causes resistance to chemo- and radio-therapy. Targeting the EGFR with Erlotinib, in combination with gemcitabine, improves survival but the modest clinical response makes the search for mechanisms to improve this response of critical clinical interest. The acidic tumor microenvironment that results from hypoxia evokes compensatory changes in the cancer cell that confers survival, growth advantages and increased invasion. The Na+/H+ exchanger, NHE1, one of the predominant regulators of tumor intracellular/extracellular pH (pHi/pHe), is hyperactivated in tumor cells and mediates multiple pH-dependent processes including stimulation of migration, increased invasion through altered invadopodia tumor cell-ECM interactions, MMPs activity and secretion of ECM proteins. Importantly, in other tumor types hypoxia increases NHE1 expression via HIF-1 and EGF activates NHE1, exacerbating extracellular acidosis and increasing invasion and ECM proteolysis. However, the role and interaction of these proteins in PDAC is still unknown.
Results. Data mining of a large pancreatic gene data base with the EGAN software revealed a strong interaction of the EGFR with NHE1 in PDAC, suggesting an important role of the NHE1 in transducing the EGFR signal. This hypothesis was confirmed in a series of experiments. We found that NHE1 expression and activity levels follow the aggressivity of a panel of five PDAC human cell lines representing distinct phases of neoplastic progression. Further, experiments with the specific NHE1 inhibitor cariporide (HOE 642) demonstrated that NHE1 plays an important role in both basal and EGF-stimulated 3D colony growth, invasion and invadopodia-dependent ECM digestive ability. Altogether, these data demonstrate a critical role of NHE1 in the induction of the PDAC metastatic process. Moreover, we show that NHERF1, a component of the hypoxia-driven up-regulation of NHE1 activity and invasion, is physically complexed with both EGFR and NHE1 after EGF stimulation in the same cell line and in pancreatic tumor xenografts developed by implanting the same cell lines in nude mice, indicating that in PDAC EGFR activation by EGF stimulates the formation of an altered NHE1/EGFR/NHERF1 axis. The overexpression of NHERF1 increased the cells ECM proteolytic response to EGF and this was greatly reduced by cariporide treatment.
Conclusions. Altogether, these data demonstrate that targeting NHE1/NHERF1 function together with the EGFR may offer an additional basis for developing innovative therapeutic strategies to, at least partially, overcome the current treatment failure.
Acknowledgements
KZ, AZ and MS are doctoral fellows of the Marie Curie 'IonTraC' project.
Keywords:
3D growth,
invasion,
invadopodia,
EGFR,
NHERF1
Conference:
4th Annual Meeting of the International Society of Proton Dynamics in Cancer, Garching, Germany, 10 Oct - 12 Oct, 2013.
Presentation Type:
Abstract
Topic:
7. pH and stroma-tumor interactions, metastasis
Citation:
Cardone
RA,
Greco
MR,
Zeeberg
K,
Zaccagnino
A,
Saccomano
M,
Menga
M,
Alves
F,
Kalthoff
H,
Casavola
V and
Reshkin
SJ
(2014). The Na+/H+ exchanger (NHE1) is an essntial component of the EGFR pathway in pancreatic ductual adenocarcinoma (PDAC) and is a new target for combination therapy.
Front. Pharmacol.
Conference Abstract:
4th Annual Meeting of the International Society of Proton Dynamics in Cancer.
doi: 10.3389/conf.fphar.2014.61.00012
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Received:
17 Jan 2014;
Published Online:
07 Feb 2014.
*
Correspondence:
Dr. Stephan J Reshkin, University of Bari, Bari, Italy, stephanjoel.reshkin@uniba.it