Defining COMMD4 as an anti-cancer therapeutic target and prognostic factor in non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancers (NSCLC) account for 85-90% of all lung cancers. As drug resistance critically impairs chemotherapy effectiveness, there is great need to identify new therapeutic targets. The aims of this study were to investigate the prognostic and therapeutic potential of the copper-metabolism-domain-protein, COMMD4, in NSCLC. METHODS: The expression of COMMD4 in NSCLC was investigated using bioinformatic analysis, immunoblotting of immortalised human bronchial epithelial (HBEC) and NSCLC cell lines, qRT-PCR and immunohistochemistry of tissue microarrays. COMMD4 function was additionally investigated in HBEC and NSCLC cells depleted of COMMD4, using small interfering RNA sequences. RESULTS: Bioinformatic analysis and in vitro analysis of COMMD4 transcripts showed that COMMD4 levels were upregulated in NSCLC and elevated COMMD4 was associated with poor prognosis in adenocarcinoma (ADC). Immunoblotting demonstrated that COMMD4 expression was upregulated in NSCLC cells and siRNA-depletion of COMMD4, decreased cell proliferation and reduced cell viability. Cell death was further enhanced after exposure to DNA damaging agents. COMMD4 depletion caused NSCLC cells to undergo mitotic catastrophe and apoptosis. CONCLUSIONS: Our data indicate that COMMD4 may function as a prognostic factor in ADC NSCLC. Additionally, COMMD4 is a potential therapeutic target for NSCLC, as its depletion induces cancer cell death.

Che-1 phosphorylation by ATM/ATR and Chk2 kinases activates p53 transcription and the G2/M checkpoint.

Che-1 is a RNA polymerase II-binding protein involved in the transcription of E2F target genes and induction of cell proliferation. Here we show that Che-1 contributes to DNA damage response and that its depletion sensitizes cells to anticancer agents. The checkpoint kinases ATM/ATR and Chk2 interact with Che-1 and promote its phosphorylation and accumulation in response to DNA damage. These Che-1 modifications induce a specific recruitment of Che-1 on the TP53 and p21 promoters. Interestingly, it has a profound effect on the basal expression of p53, which is preserved following DNA damage. Notably, Che-1 contributes to the maintenance of the G2/M checkpoint induced by DNA damage. These findings identify a mechanism by which checkpoint kinases regulate responses to DNA damage.

COMMD1, from the Repair of DNA Double Strand Breaks, to a Novel Anti-Cancer Therapeutic Target.

Lung cancer has the highest incidence and mortality among all cancers, with non-small cell lung cancer (NSCLC) accounting for 85-90% of all lung cancers. Here we investigated the function of COMMD1 in the repair of DNA double strand breaks (DSBs) and as a prognostic and therapeutic target in NSCLC. COMMD1 function in DSB repair was investigated using reporter assays in COMMD1-siRNA-depleted cells. The role of COMMD1 in NSCLC was investigated using bioinformatic analysis, qRT-PCR and immunoblotting of control and NSCLC cells, tissue microarrays, cell viability and cell cycle experiments. DNA repair assays demonstrated that COMMD1 is required for the efficient repair of DSBs and reporter assays showed that COMMD1 functions in both non-homologous-end-joining and homologous recombination. Bioinformatic analysis showed that COMMD1 is upregulated in NSCLC, with high levels of COMMD1 associated with poor patient prognosis. COMMD1 mRNA and protein were upregulated across a panel of NSCLC cell lines and siRNA-mediated depletion of COMMD1 decreased cell proliferation and reduced cell viability of NSCLC, with enhanced death after exposure to DNA damaging-agents. Bioinformatic analyses demonstrated that COMMD1 levels positively correlate with the gene ontology DNA repair gene set enrichment signature in NSCLC. Taken together, COMMD1 functions in DSB repair, is a prognostic maker in NSCLC and is potentially a novel anti-cancer therapeutic target for NSCLC.

Chemotherapeutic compounds targeting the DNA double-strand break repair pathways: the good, the bad, and the promising.

The repair of DNA double-strand breaks (DSBs) is a critical cellular mechanism that exists to ensure genomic stability. DNA DSBs are the most deleterious type of insult to a cell's genetic material and can lead to genomic instability, apoptosis, or senescence. Incorrectly repaired DNA DSBs have the potential to produce chromosomal translocations and genomic instability, potentially leading to cancer. The prevalence of DNA DSBs in cancer due to unregulated growth and errors in repair opens up a potential therapeutic window in the treatment of cancers. The cellular response to DNA DSBs is comprised of two pathways to ensure DNA breaks are repaired: homologous recombination and non-homologous end joining. Identifying chemotherapeutic compounds targeting proteins involved in these DNA repair pathways has shown promise as a cancer therapy for patients, either as a monotherapy or in combination with genotoxic drugs. From the beginning, there have been a number of chemotherapeutic compounds that have yielded successful responses in the clinic, a number that have failed (CGK-733 and iniparib), and a number of promising targets for future studies identified. This review looks in detail at how the cell responds to these DNA DSBs and investigates the chemotherapeutic avenues that have been and are currently being explored to target this repair process.