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.
Highlights
Prostaglandin E2 (PGE2) promotes tumor growth by inducing an inflammatory microenvironment, in autocrine or paracrine fashion, through the activation of 4 receptor subtypes: EP1, EP2, EP3, EP4 [1,2,3]
Clathrin- and Caveolin-mediated endocytosis are both dependent on the activity of the large guanosine 5′-triphosphatase (GTPase) dynamin [21], whereas macropinocytosis is susceptible to Na+/H+ exchange inhibitors, such as amiloride [22]
Immunofluorescence staining followed by confocal microscopy analysis showed that in control conditions and in non-small cell lung carcinoma (NSCLC) cells treated with DYN or Ethyl-N-isopropyl amiloride (EIPA) alone, Epidermal growth factor receptor (EGFR) was confined to the cell membrane (Figure 1D)
Summary
Prostaglandin E2 (PGE2) promotes tumor growth by inducing an inflammatory microenvironment, in autocrine or paracrine fashion, through the activation of 4 receptor subtypes: EP1, EP2, EP3, EP4 [1,2,3]. We have recently reported that PGE2 induces EGFR internalization and nuclear translocation supporting tumor progression in non-small cell lung cancer (NSCLC). We have shown that PGE2-induced EGFR transactivation promotes its nuclear import and the subsequent SRC/ADAMs-mediated autocrine and/or www.oncotarget.com paracrine release of soluble cell-surface EGF like ligands, an event that culminates in EGFR-mediated transcriptional activities and enhanced tumor cell proliferation [12]. EGFR undergoes either Clathrin-mediated endocytosis (CME) or Clathrin-independent endocytosis (CIE), including lipid-raft dependent routes, such as Caveolin-mediated endocytosis and macropinocytosis [15]. EGFR is mainly internalized via Clathrin- mediated endocytosis [16], yet saturation of Clathrin or stimulation with different ligands has been shown to induce alternative routes of internalization, including Caveolin-mediated endocytosis and macropinocytosis [17,18,19]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
