Mechanistic Studies of the Multiple Myeloma and Melanoma Cell-Selective Toxicity of the Rpn13-Binding Peptoid KDT-11. Issue 11 (19th November 2020)

• Record Type: Journal Article
• Authors: Dickson, Paige; Simanski, Scott; Ngundu, John Maina; Kodadek, Thomas
• Is Part Of: Cell chemical biology. Volume 27:Issue 11(2020)
• Page Start: 1383
• Page End: 1395.e5
• Publication Date: 2020-11-19
• Subjects: Rpn13 -- Uch37 -- peptoid -- proteasome -- multiple myeloma -- cancer -- combinatorial chemistry -- cell cycle; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2020.08.008
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: We previously reported a peptoid ligand for the proteasomal ubiquitin receptor Rpn13 called KDT-11 and demonstrated that this compound is toxic to multiple myeloma cells, but not non-malignant cells. Here, we show that KDT-11 decreases the viability of a variety of cancer cell lines, especially melanomas and various blood cancers. The peptoid induces selective G1 cell-cycle arrest, resulting in eventual apoptosis. While KDT-11 does not antagonize any of the known protein-protein interactions involving Rpn13, the peptoid inhibits the ability of Rpn13 to stimulate the activity of an associated deubiquitylase Uch37/UCHL5 in vitro, suggesting a high level of Uch37 activity might be important for cancer cell proliferation. However, a variety of experiments in SK-MEL-5 melanoma cells suggest that KDT-11's cytotoxic effects are mediated by interactions with proteins other than Rpn13. Graphical Abstract: Highlights: Peptidomimetic KDT-11 induces cancer-selective G1/S cell-cycle arrest KDT-11 does not disrupt its reported target Rpn13's known protein interactions Cellular sensitivity to KDT-11 does not relate to Rpn13 protein level Abstract : Dickson et al. characterize the mechanism of action of peptidomimetic KDT-11, previously reported to bind Rpn13 and reduce viability of cancer cells. Through biochemical and cellular approaches, the group demonstrates that KDT-11 does not disrupt Rpn13's known protein interactions, nor is cellular sensitivity to KDT-11 correlated with Rpn13 levels.