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  • Original Paper
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Combined treatment with EGFR inhibitors and arsenite upregulated apoptosis in human EGFR-positive melanomas: a role of suppression of the PI3K-AKT pathway

Oncogene volume 24, pages 616–626 (2005)Cite this article

Abstract

Epidermal growth factor receptor (EGFR) is expressed, albeit at low or intermediate levels, in human melanomas at the different stages of tumor progression. Coexpression of EGFR with its ligand TGFα indicates their role in paracrine and autocrine growth regulation of melanomas. As it was previously observed for several types of cancer, specific inhibitors of EGFR-mediated signaling may reduce antiapoptotic properties of cancer cells and sensitize them to cytotoxic drugs. We recently reported that arsenite, particularly in combination with inhibitors of the PI3K-AKT and mitogen-activated protein kinase (MAPK) kinase (MEK)-extracellular signal-regulated kinase (ERK) pathways, induces high levels of apoptosis in different melanomas. Since EGFR signaling operates via activation of the PI3K-AKT and MEK-ERK pathways, we suggested that the combination of arsenite and EGFR inhibitors might also effectively induce apoptosis in melanoma. Here, we demonstrate that a moderate concentration of arsenite (5–10 μ M) indeed upregulates apoptosis induced by EGFR inhibitors in EGFR-positive melanomas. In contrast, induction of apoptosis in melanomas with negligible surface expression of EGFR or with defective EGFR signaling requires direct suppression of the PI3K-AKT and MAPK pathways by specific pharmacological inhibitors in the presence of arsenite. Under these conditions, metastatic melanoma cell lines undergo TNF-related apoptosis-inducing ligand (TRAIL)- and tumor necrosis factor alpha (TNFα)-mediated apoptosis. Taken together, these data provide additional approaches in sensitizing melanomas to the cytotoxic effects of specific inhibitors of survival pathways.

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Abbreviations

Ac-IETD-CHO:

N-acetyl-Ile-Glu-Thr-Asp-CHO (aldehyde)

Ac-LEHD-CHO:

N-acetyl-Leu-Glu-His-Asp-CHO (aldehyde)

AP-1:

activator protein-1

ATF2:

activating transcription factor 2

EGFR:

epidermal growth factor receptor

EMSA:

electrophoretic mobility shift assay

ERK:

extracellular signal-regulated kinase

FACS:

fluorescence-activated cell sorter

HO-1:

heme oxygenase-1

JNK:

Jun N-terminal kinase

IκB:

inhibitor of NF-κB

IKK:

inhibitor nuclear factor kappa B kinase

MAPK:

mitogen-activated protein kinase

MEK:

MAPK kinase

MFI:

medium fluorescence intensity

mTOR:

mammalian target of rapamycin

NF-κB:

nuclear factor kappa B

PARP:

poly (ADP-ribose) polymerase

PI:

propidium iodide

PP IX (Zn2+):

Zn-containing protoporphyrin IX

ROS:

reactive oxygen species

TNFα:

tumor necrosis factor alpha

TNFR:

tumor necrosis factor receptor

TRAIL:

TNF-related apoptosis-inducing ligand

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Acknowledgements

This work was supported by NIH Grant ES 11804, ES 05786 Superfund Grant P42 ES 10349 and Environmental Center Grant P30 ES 09089. We thank Drs M Herlyn, O Fodstad, R Halaban and Z Ronai for the cell lines; Dr A Chan, Dr S Fuchs, Ms S Baker and Mr JA Gillespie for critical reading of the manuscript.

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  1. Center for Radiological Research, Columbia University College of Physicians and Surgeons, 630 West 168-th St, VC11-218, New York, NY, 10032, USA

    Vladimir N Ivanov & Tom K Hei

  2. Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, 10032, USA

    Tom K Hei

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Correspondence to Vladimir N Ivanov.

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Ivanov, V., Hei, T. Combined treatment with EGFR inhibitors and arsenite upregulated apoptosis in human EGFR-positive melanomas: a role of suppression of the PI3K-AKT pathway. Oncogene 24, 616–626 (2005). https://doi.org/10.1038/sj.onc.1208125

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