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FIGURE 1 from A Novel Class of Ribosome Modulating Agents Exploits Cancer Ribosome Heterogeneity to Selectively Target the CMS2 Subtype of Colorectal Cancer

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posted on 2023-06-05, 14:20 authored by Esteban Terzo, Shruti A. Apte, Simran Padhye, Saleh Rashed, Wesley Austin, Michael Caponegro, Anupama Reddy, Shuhao Shi, Christy Wang, Roger B. Clark, David Sidransky, Vijay Modur, Vasudeo Badarinarayana

ZKN-157 selectively inhibits growth and protein translation in a sensitive colorectal cancer cell line. A, Chemical structure of ZKN-157. B, Percent response curves showing the effect of ZKN-157 treatment in COLO320DM and SW1417 cells. Curves are representative of three independent biological experiments. Error bars are SDs of two technical replicates. Table shows GI50 and LD50 values C, Cartoon showing the metabolic labeling assay workflow. D, Representative Western blot membranes of two independent biological experiments showing: -AHA (no AHA reagent added to lysate), CHX (positive control for translation inhibition), DMSO (negative control), and ZKN-157 treatment (40 μmol/L). Equal protein amount for all samples were used for click chemistry reaction. Samples resuspended in equal volume were loaded on gel. Intensity from densitometry of ZKN-157–treated samples was normalized to those of DMSO samples to calculate relative protein translation. Bar graph shows normalized values from two independent experiments. Error bars are SDs.

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ARTICLE ABSTRACT

This study demonstrates that ribosome heterogeneity in cancer can be exploited to develop selective ribogenesis inhibitors. The colorectal cancer CMS2 subtype, with a high unmet need for therapeutics, shows vulnerability to our novel selective ribosome modulator. The mechanism suggests that other cancer subtypes with high MYC activation could also be targeted.

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