title: 1, 9-Pyrazoloanthrones downregulate HIF-1α and sensitize cancer cells to cetuximab-mediated anti-EGFR therapy.
abstract: 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-1α) 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-1α independently of its inhibition of JNK. This downregulatory effect was abolished when the oxygen-dependent domain (ODD) of HIF-1α (HIF-1α-ΔODD, the domain responsible for HIF-1α degradation) was experimentally deleted or when the activity of HIF-1α prolyl hydroxylase (PHD) or the 26S proteasomal complex was inhibited, indicating that the 1, 9 PA downregulates HIF-1α by promoting PHD-dependent HIF-1α 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-1α-ΔODD, indicating that downregulation of HIF-1α was the mechanism of this synergistic effect. More importantly, 1, 9 PA can downregulate HIF-1α in cancer cells that are insensitive to cetuximab-induced inhibition of HIF-1α 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-1α.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.forename: Xinqun
authors.initials: X
authors.lastname: Li
authors.forename: Haiquan
authors.initials: H
authors.lastname: Lu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Fan
mesh_terms: D000873:Anthracenes / Q000737:chemistry* / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D000068818:Cetuximab; D015536:Down-Regulation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D009154:Mutation; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology*; D025801:Ubiquitin / Q000737:chemistry; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000873:Anthracenes; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D051793:Hypoxia-Inducible Factor 1; D011720:Pyrazoles; D025801:Ubiquitin; D042461:Vascular Endothelial Growth Factor A; D066246:ErbB Receptors; D048670:MAP Kinase Kinase 4; D000068818:Cetuximab