These agents have been proven to induce development suppression, apoptosis, and/or chemo- and radiosensitization in HNSCC cells and xenograft tumors . Cetuximab combined with radiation has recently been shown to improve locoregional management and reduce mortality , and was accredited by FDA because the to begin with new therapy during the final 45 many years for HNSCC sufferers . Despite encouraging developments, EGFR-targeted therapies only job inside a rather modest percentage of cancer patients . The critical intracellular molecular targets as well as mechanism underlying variable responses to these therapies remain elusive. The BH3-only protein PUMA , was initially recognized as a vital mediator of apoptosis induced by the tumor suppressor p53 and DNA damaging agents . PUMA plays an essential purpose in p53-dependent and -independent apoptosis in human cancer cells and mice, and mediates apoptosis with the Bcl-2 family proteins Bax/Bak along with the mitochondrial pathway .
A few studies have convincingly proven that PUMA induction by DNA damage is totally dependent on an intact p53 gene and it is mediated through the two p53-responsive elements in its promoter . On the other hand, PUMA can be induced by non-genotoxic stimuli such as kinase activators, endoplasmic reticulum poisons, cytokine withdrawal and growth issue deprivation in PS-341 several cell sorts independent of p53 . Current research from us and some others have proven that transcription factors this kind of as p73, Sp1 and FoxO3a regulate PUMA induction soon after serum starvation or cytokine withdrawal in colon cancer cells and lymphocytes, respectively . On this review, we noticed that PUMA is induced by three EGFR-targeting agents independent of p53 in HNSCC cells.
Even more investigation suggested that PUMA functions as being a significant mediator of EGFR inhibitor-induced apoptosis in head and neck cancer cells, the place p53 loved ones proteins such as p73, p63, and also the PI3K/AKT pathway serve as crucial regulators of PUMA induction following article source EGFR inhibition. Our research provides a molecular mechanism of apoptosis induced by EGFR-targeted therapies in head and neck cancer cells. PUMA is regularly expressed at low basal amounts and will be induced by the two genotoxic and non-genotoxic stresses . As >80% of HNSCC overexpress EGFR, we chose to examine PUMA levels after the inhibition of EGFR signaling. HNSCC cell lines had been treated with 3 regularly implemented EGFR-targeting agents, like the TKIs gefitinib and erlotinib, and also the EGFR monoclonal antibody cetuximab.
We discovered that PUMA was induced by gefitinib while in the majority of HNSCC lines tested , 6 of which incorporate mutant p53 . Erlotinib and cetuximab also induced PUMA in eight HNSCC cell lines tested . You can find at least 4 species of PUMA transcripts on account of choice splicing.