%0 Journal Article
%T 1, 9-Pyrazoloanthrones Downregulate HIF-1¦Á and Sensitize Cancer Cells to Cetuximab-Mediated Anti-EGFR Therapy
%A Yang Lu
%A Xinqun Li
%A Haiquan Lu
%A Zhen Fan
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0015823
%X Cetuximab, a monoclonal antibody that blocks the epidermal growth factor receptor (EGFR), is currently approved for the treatment of several types of solid tumors. We previously showed that cetuximab can inhibit hypoxia-inducible factor-1 alpha (HIF-1¦Á) protein synthesis by inhibiting the activation of EGFR downstream signaling pathways including Erk, Akt, and mTOR. 1, 9-pyrazoloanthrone (1, 9 PA) is an anthrapyrazolone compound best known as SP600125 that specifically inhibits c-jun N-terminal kinase (JNK). Here, we report 1, 9 PA can downregulate HIF-1¦Á independently of its inhibition of JNK. This downregulatory effect was abolished when the oxygen-dependent domain (ODD) of HIF-1¦Á (HIF-1¦Á-¦¤ODD, the domain responsible for HIF-1¦Á degradation) was experimentally deleted or when the activity of HIF-1¦Á prolyl hydroxylase (PHD) or the 26S proteasomal complex was inhibited, indicating that the 1, 9 PA downregulates HIF-1¦Á by promoting PHD-dependent HIF-1¦Á degradation. We found that the combination of 1, 9 PA and cetuximab worked synergistically to induce apoptosis in cancer cells in which cetuximab or 1, 9 PA alone had no or only weak apoptotic activity. This synergistic effect was substantially decreased in cancer cells transfected with HIF-1¦Á-¦¤ODD, indicating that downregulation of HIF-1¦Á was the mechanism of this synergistic effect. More importantly, 1, 9 PA can downregulate HIF-1¦Á in cancer cells that are insensitive to cetuximab-induced inhibition of HIF-1¦Á expression due to overexpression of oncogenic Ras (RasG12V). Our findings suggest that 1, 9 PA is a lead compound of a novel class of drugs that may be used to enhance the response of cancer cells to cetuximab through a complementary effect on the downregulation of HIF-1¦Á.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0015823