Blocking HIF signaling via novel inhibitors of CA9 and APE1/Ref-1 dramatically affects pancreatic cancer cell survival

Scientific Reports
Derek P LogsdonMelissa L Fishel

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has reactive stroma that promotes tumor signaling, fibrosis, inflammation, 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 effector 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 differential hypoxic responses in 3D spheroid tumor-stroma models to characterize second generation APE1/Ref-1 redox signaling and CA9 inhibitors. Our data demonstrates that HIF-1α-mediated CA9 induction differs 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...Continue Reading

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Citations

Jan 9, 2020·Scientific Reports·Dilara AyyildizSilvano Piazza
Aug 23, 2020·International Journal of Molecular Sciences·Bor-Ren HuangDah-Yuu Lu
Sep 22, 2020·Journal of Dermatological Science·Xuyi DengMeijuan Zhou
Jan 14, 2021·Journal of Hematology & Oncology·Jinxin TaoYupei Zhao
Nov 6, 2020·Drug Discovery Today·Rachel A CastonMark R Kelley
Aug 12, 2021·Journal of Experimental & Clinical Cancer Research : CR·Silpa GampalaMelissa L Fishel

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Methods Mentioned

BETA
Immunoprecipitation
ChIP
Immunoprecipitations
scRNA-Seq
RNA-Seq
xenograft

Clinical Trials Mentioned

NCT02215850
NCT03450018
NCT03375086

Software Mentioned

Prism
GraphPad
Excel

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