PML involvement in the p73-mediated E1A-induced suppression of EGFR and induction of apoptosis in head and neck cancers

Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase is commonly overexpressed in human cancers; however, the cellular mechanisms regulating EGFR expression remain unclear. p53, p63 and p73 are transcription factors regulating many cellular targets involved in controlling the cell cycle and apoptosis. p53 activates EGFR expression, whereas TAp63 represses EGFR transcription. The involvement of p73 in the regulation of EGFR has not been reported. Here, a strong correlation between EGFR overexpression and increased levels of the oncogenic DNp73 isoform in head and neck squamous cell carcinoma (HNSCC) cell lines was observed. Ectopic expression of TAp73, particularly TAp73b, resulted in suppression of the EGFR promoter, significant downregulation of EGFR protein and efficient induction of cell death in all six EGFR-overexpressing HNSCC cell lines. EGFR overexpression from a heterologous LTR promoter protected lung cancer cells from TAp73b-induced EGFR suppression and apoptosis. Expression of TAp73b efficiently induced promyelocytic leukaemia (PML) protein expression and PML knockdown by shRNA attenuated the downregulation of EGFR and induction of apoptosis by p73 in HNSCC cells. Furthermore, PML was found to be important for E1A-induced suppression of EGFR and subsequent killing of HNSCC cells. Our data therefore suggest a novel pathway involving PML and p73 in the regulation of EGFR expression.

The guardians of the genome (p53, TA-p73, and TA-p63) are regulators of tumor suppressor miRNAs network

“…4) [53,59]. These data suggest a possibility that TA-p63γ/p73β, by inhibiting the expression of oncogenic EGFR, it could inhibit the TWIST expression, and thereby increase the E-cadherin expression [53,147]. This in turn will result in inhibition of EMT.…”

Benzo(a)pyrene induces p73 mRNA expression and necrosis in human lung adenocarcinoma H1299 cells

“…Previous studies have reported that BaP‐induced apoptosis is associated with the p53 signaling pathway in several cell lines (Ko et al,2004; Mansoor et al,2009; Tekpli et al,2009). p73 closely mimics p53 and induces apoptosis (Klanrit et al,2009). They are each activated by different types of DNA damage (Bergamaschi et al,2004; Rocco et al,2006) and are both involved in the apoptotic response to p53‐null cells treated with certain genotoxic agents (Ramadan et al,2005).…”

Systematic review: molecular chemoprevention of colorectal malignancy by mesalazine

“…Importantly, the position of the amino group in 5‐ASA benzene ring is critical for improvement of replication fidelity 21 . As p53 activates epidermal growth factor receptor (EGFR) expression in cancer cells 22 and EGFR function is required for cell cycle progression 23,24 there are many reasons to suggest a connection between 5‐ASA‐mediated phosphorylation of p53 and EGFR status. Findings of Monteleoni’s group show 5‐ASA inhibition of EGFR signalling pathway by enhancing activity of SH‐PTP2 phosphatase 25 .…”