Oncotarget

Research Papers:

PGE2 mediates EGFR internalization and nuclear translocation via caveolin endocytosis promoting its transcriptional activity and proliferation in human NSCLC cells

Lorenzo Bazzani, Sandra Donnini, Antonio Giachetti, Gerhard Christofori and Marina Ziche _

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Oncotarget. 2018; 9:14939-14958. https://doi.org/10.18632/oncotarget.24499

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Abstract

Lorenzo Bazzani1,2, Sandra Donnini1, Antonio Giachetti1, Gerhard Christofori2 and Marina Ziche1

1Department of Life Sciences, University of Siena, Siena, Italy

2Department of Biomedicine, University of Basel, Basel, Switzerland

Correspondence to:

Marina Ziche, email: marina.ziche@unisi.it

Keywords: nuclear EGFR; PGE2; clathrin and caveolin endocytosis; gene transcription; cell proliferation

Received: September 13, 2017    Accepted: February 10, 2018    Epub: February 15, 2018    Published: March 13, 2018

ABSTRACT

Prostaglandin E2 (PGE2) contributes to tumor progression by promoting cancer cell growth, invasion and by creating a favorable pro-tumor microenvironment. PGE2 has been reported to transactivate and internalize into the nucleus receptor tyrosine kinases such as Epidermal growth factor receptor (EGFR), thereby supporting tumor progression. Here we demonstrate that in non-small cell lung carcinoma (NSCLC) cells, PGE2 induces EGFR nuclear translocation via different dynamin-dependent endocytic pathways, promotes the formation of an EGFR-STAT3 complex, affects nuclear EGFR target gene expression and mediates tumor cell proliferation. Indeed, we find that PGE2 induces EGFR internalization and consequent nuclear import through Clathrin- and Caveolin-mediated endocytosis and through the interaction of EGFR with Importin β1. Within the nucleus, EGFR forms a complex with STAT3, an event blocked by ablation of Clathrin Heavy Chain or Caveolin-1. The combination of EGF and PGE2 prolongs nuclear EGFR transcriptional activity manifested by the upregulation of CCND1, PTGS2, MYC and NOS2 mRNA levels and potentiates nuclear EGFR-induced NSCLC cell proliferation. Additionally, NSCLC patients with high expression of a nuclear EGFR gene signature display shorter survival times than those with low expression, thus showing a putative correlation between nuclear EGFR and poor prognosis in NSCLC. Together, our findings indicate a complex mechanism underlying PGE2-induced EGF/EGFR signaling and transcriptional control, which plays a key role in cancer progression.


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