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

Derek P. Logsdon, Fenil Shah, Fabrizio Carta, Claudiu T. Supuran, Malgorzata Kamocka, Max H. Jacobsen, George Sandusky, Mark Kelley, Melissa Fishel

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 that this combination effectively kills PDAC tumor cells displaying drastically different levels of CA9. New APE1/Ref-1 and CA9 inhibitors were significantly more potent alone and in combination, highlighting the potential of combination therapy targeting the APE1-Ref-1 signaling axis with significant clinical potential.

Original languageEnglish (US)
Article number13759
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

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Pancreatic Neoplasms
Cell Survival
Adenocarcinoma
Oxidation-Reduction
Neoplasms
Fibrosis
Transcription Factors
Up-Regulation
Neoplasm Metastasis
Inflammation
Hypoxia
DNA
Therapeutics
Pharmaceutical Preparations
Genes
Proteins

ASJC Scopus subject areas

  • General

Cite this

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; Kelley, Mark; Fishel, Melissa.

In: Scientific Reports, Vol. 8, No. 1, 13759, 01.12.2018.

Research output: Contribution to journalArticle

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