Pancreatic ductal adenocarcinoma (PDAC) has reactive stroma that promotes tumor signaling, fbrosis, infammation, and hypoxia, which activates HIF-1α to increase tumor cell metastasis and therapeutic resistance. Carbonic anhydrase IX (CA9) stabilizes intracellular pH following induction by HIF-1α. Redox efector factor-1 (APE1/Ref-1) is a multifunctional protein with redox signaling activity that converts certain oxidized transcription factors to a reduced state, enabling them to upregulate tumor-promoting genes. Our studies evaluate PDAC hypoxia responses and APE1/Ref-1 redox signaling contributions to HIF-1α-mediated CA9 transcription. Our previous studies implicated this pathway in PDAC cell survival under hypoxia. We expand those studies, comparing drug responses using patient-derived PDAC cells displaying diferential hypoxic responses in 3D spheroid tumor-stroma models to characterize second generation APE1/Ref-1 redox signaling and CA9 inhibitors. Our data demonstrates that HIF1α-mediated CA9 induction difers between patient-derived PDAC cells and that APE1/Ref-1 redox inhibition attenuates this induction by decreasing hypoxia-induced HIF-1 DNA binding. Dual-targeting of APE1/Ref-1 and CA9 in 3D spheroids demonstrated that this combination efectively kills PDAC tumor cells displaying drastically diferent levels of CA9. New APE1/Ref-1 and CA9 inhibitors were signifcantly more potent alone and in combination, highlighting the potential of combination therapy targeting the APE1-Ref-1 signaling axis with signifcant clinical potential
Blocking HIF signaling via novel inhibitors of CA9 and APE1/Ref-1 dramatically affects pancreatic cancer cell survival / Logsdon, Derek P.; Shah, Fenil; Carta, Fabrizio; Supuran, Claudiu T.; Kamocka, Malgorzata; Jacobsen, Max H.; Sandusky, George E.; Kelley, Mark R.; Fishel, Melissa L.. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - ELETTRONICO. - 8:(2018), pp. 13759-13773. [10.1038/s41598-018-32034-9]
Blocking HIF signaling via novel inhibitors of CA9 and APE1/Ref-1 dramatically affects pancreatic cancer cell survival
Carta, Fabrizio;Supuran, Claudiu T.;
2018
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has reactive stroma that promotes tumor signaling, fbrosis, infammation, and hypoxia, which activates HIF-1α to increase tumor cell metastasis and therapeutic resistance. Carbonic anhydrase IX (CA9) stabilizes intracellular pH following induction by HIF-1α. Redox efector factor-1 (APE1/Ref-1) is a multifunctional protein with redox signaling activity that converts certain oxidized transcription factors to a reduced state, enabling them to upregulate tumor-promoting genes. Our studies evaluate PDAC hypoxia responses and APE1/Ref-1 redox signaling contributions to HIF-1α-mediated CA9 transcription. Our previous studies implicated this pathway in PDAC cell survival under hypoxia. We expand those studies, comparing drug responses using patient-derived PDAC cells displaying diferential hypoxic responses in 3D spheroid tumor-stroma models to characterize second generation APE1/Ref-1 redox signaling and CA9 inhibitors. Our data demonstrates that HIF1α-mediated CA9 induction difers between patient-derived PDAC cells and that APE1/Ref-1 redox inhibition attenuates this induction by decreasing hypoxia-induced HIF-1 DNA binding. Dual-targeting of APE1/Ref-1 and CA9 in 3D spheroids demonstrated that this combination efectively kills PDAC tumor cells displaying drastically diferent levels of CA9. New APE1/Ref-1 and CA9 inhibitors were signifcantly more potent alone and in combination, highlighting the potential of combination therapy targeting the APE1-Ref-1 signaling axis with signifcant clinical potentialFile | Dimensione | Formato | |
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Logsdon, D.P.a_Blocking-HIF-signaling-via-novel-inhibitors-of-CA9-and-APE1Ref1-dramatically-affects-pancreatic-cancer-cell-survivalArticleOpen-Access_2018.pdf
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