STAT1 activation is enhanced by cisplatin and variably affected by EGFR inhibition in HNSCC cells

Nicole Schmitt, Sumita Trivedi, Robert L. Ferris

Research output: Contribution to journalArticle

Abstract

Cisplatin is a cytotoxic chemotherapeutic drug frequently used to treat many solid tumors, including head and neck squamous cell carcinoma (HNSCC). EGF receptor (EGFR) inhibitors have also shown efficacy as alternatives to cisplatin in some situations. However, large clinical trials have shown no added survival benefit from the use of these two drugs in combination. Possible explanations for this include overlapping downstream signaling cascades. Using in vitro studies, we tested the hypothesis that cisplatin and EGFR inhibitors rely on the activation of the tumor suppressor STAT1, characterized by its phosphorylation at serine (S727) or tyrosine (Y701) residues. Cisplatin consistently increased the levels of p-S727-STAT1, and STAT1 siRNA knockdown attenuated cisplatin-induced cell death. EGFR stimulation also activated p-S727-STAT1 and p-Y701-STAT1 in a subset of cell lines, whereas EGFR inhibitors alone decreased levels of p-S727-STAT1 and p-Y701-STAT1 in these cells. Contrary to our hypothesis, EGFR inhibitors added to cisplatin treatment caused variable effects among cell lines, with attenuation of p-S727-STAT1 and enhancement of cisplatin-induced cell death in some cells and minimal effect in other cells. Using HNSCC tumor specimens from a clinical trial of adjuvant cisplatin plus the anti-EGFR antibody panitumumab, higher intratumoral p-S727-STAT1 appeared to correlate with worse survival. Together, these results suggest that cisplatin-induced cell death is associated with STAT1 phosphorylation, and the addition of anti-EGFR therapy to cisplatin has variable effects on STAT1 and cell death in HNSCC.

Original languageEnglish (US)
Pages (from-to)2103-2111
Number of pages9
JournalMolecular Cancer Therapeutics
Volume14
Issue number9
DOIs
StatePublished - Sep 1 2015
Externally publishedYes

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Epidermal Growth Factor Receptor
Cisplatin
Cell Death
Phosphorylation
Carcinoma, squamous cell of head and neck
Clinical Trials
Cell Line
Neoplasms
Drug Combinations
Serine
Small Interfering RNA
Tyrosine
Antibodies

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

STAT1 activation is enhanced by cisplatin and variably affected by EGFR inhibition in HNSCC cells. / Schmitt, Nicole; Trivedi, Sumita; Ferris, Robert L.

In: Molecular Cancer Therapeutics, Vol. 14, No. 9, 01.09.2015, p. 2103-2111.

Research output: Contribution to journalArticle

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