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Inhibition of HIF Signal Transduction and NFkB Activation in Cancer Cells

This study investigates the inhibition of Hypoxia-Inducible Factor (HIF) signal transduction and its effect on gene transactivation, specifically focusing on BNIP3 mRNA levels. The effects of various compounds, including AJM290 and AW464, on protein expression (CA-IX, BNIP3) under hypoxic and normoxic conditions are examined. Additionally, we assess the inhibition of NFkB activation at multiple levels, including IK kinase activity and nuclear translocation, in HCT116 cells, revealing critical interactions in cancer cell signaling pathways.

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Inhibition of HIF Signal Transduction and NFkB Activation in Cancer Cells

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  1. Inhibition of HIF signal transduction A) Inhibition of HRE-HIF-1α DNA binding. Dose-dependent down-regulation of hypoxia-induced gene transactivation (BNIP3 mRNA) by B) AW 464 C) AJM 290 and D) protein (CA-IX, BNIP3) expression. D A 1. Cos 7/CoCl2 2. MDA 468 Nx 3. MDA 468 Hx 4. MDA 468 Hx 10 μM AJM 290 5. MDA 468 Hx 10 μM AW 464 6. Cos 7/CoCl2 + 500 ng cmpt oligo 7. MDA 468 + 500 ng cmpt oligo. IL-1β alone B PMX 464 + IL-1β C E F RCC4 + VHL N Hypoxia AJM290 AW464 C C 1 2.5 10 1 2.5 10 μM Normoxia Hypoxia C 1.0 2.5 10 C 1.0 2.5 10 μM AJM 290 AW 464 BNIP3 CA-IX Inhibition of NFkB activation Inhibition of A) IK kinase activity C) IKB phosphorylation D) nuclear translocation E) DNA binding and F) NFkB-activated transcription. A A C B D .

  2. whole cell lysates IP: Trx  p54  p54 phospho-JNK  p46  p46  ASK-1 total JNK  Trx DMSO 1 DMSO 1 DMSO 2 DMSO 2 5mM AJM 290 5mM AJM 290 5mM AW 464 5mM AW 464 actin DMSO 0.5 1 5 10 0 5 30 60 180 180 min DMSO 3h AW 464 (mM) AW 464 (5mM) AW 464 induced ASK-1/Trx dissociation and JNK activation in HCT116 cells.

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