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Fig. 4

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ZDB-FIG-220725-10

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Nunes et al., 2022 - RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition

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Fig. 4

Fig. 4. Comparative RNR inhibitor analysis to kill neuroblastoma cells.

(A) 3AP treatment can establish lower half-maximal inhibitory concentrations than gemcitabine and HU in a panel of neuroblastoma cell lines, with MYCN-amplified cell lines and the nonamplified CLB-GA cell line being more sensitive than MYCN-nonamplified cell lines (red: MYCN amplified, adrenergic; orange: MYCN nonamplified, adrenergic; blue: MYCN nonamplified, mesenchymal). (B) 3AP sensitivity (AUC) is negatively correlated to RRM2 mRNA expression levels in a panel of neuroblastoma cell lines. (C) Treatment of IMR-32 and CLB-GA neuroblastoma cells with 3AP at their respective half-maximal inhibitory concentration significantly reduces cell confluence and (D) induces cell death. (E) Nonmalignant murine NIH3T3 fibroblasts did not show reduced confluence or apoptosis induction upon 3AP exposure. (F) IC₃₀ values for IMR-32 and CLB-GA neuroblastoma cells impose a significant S phase cell cycle arrest. (G) Endogenous dNTP pools are reduced upon exposure of IMR-32 neuroblastoma cells to 3AP. (H) 3AP (IC₅₀) treatment leads to a significant increased CDKN1A and RRM2B expression. (I) DNA combing following exposure of IMR-32 neuroblastoma cells to HU or 3AP shows a significant increased levels of stalled forks upon 3AP treatment versus controls. IdU, 5′-iododeoxyuridine. (J) Immunoblotting for DNA damage response markers (pRPA32 and yH2A) and CHK1/^S345pCHK1 in protein extracts of neuroblastoma cells treated with fixed IC₃₀ and IC₅₀ of 3AP (for quantification, see fig. S2). CIdU, 5-chloro-2’-deoxyuridine.

Expression Data

Expression Detail

Antibody Labeling

Phenotype Data

Phenotype Detail

Acknowledgments

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