Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

Rate of Ubiquitination and Proteasomal Degradation of Topoisomerase I Determines Cellular Resistance to Cancer Drug

Elizabeth C Unan
,
Hiroya Matsuoka
,
Hirofumi Hasuda
,
Soumya Malhotra
,
Siddhartha Pulukuri
ORCID logo ,
Victor Bacelar
,
Allison Berger
,
Nibedita Chattopadhyay
,
Lawrence Dick
,
Eiji Oki
,
Koji Ando
,
Ajit Bharti
*
Version 1 : Received: 20 April 2021 / Approved: 28 April 2021 / Online: 28 April 2021 (08:44:34 CEST)

How to cite: Unan, E.C.; Matsuoka, H.; Hasuda, H.; Malhotra, S.; Pulukuri, S.; Bacelar, V.; Berger, A.; Chattopadhyay, N.; Dick, L.; Oki, E.; Ando, K.; Bharti, A. Rate of Ubiquitination and Proteasomal Degradation of Topoisomerase I Determines Cellular Resistance to Cancer Drug. Preprints 2021, 2021040733. https://doi.org/10.20944/preprints202104.0733.v1 Unan, E.C.; Matsuoka, H.; Hasuda, H.; Malhotra, S.; Pulukuri, S.; Bacelar, V.; Berger, A.; Chattopadhyay, N.; Dick, L.; Oki, E.; Ando, K.; Bharti, A. Rate of Ubiquitination and Proteasomal Degradation of Topoisomerase I Determines Cellular Resistance to Cancer Drug. Preprints 2021, 2021040733. https://doi.org/10.20944/preprints202104.0733.v1

Abstract

Abstract: Targeted ubiquitination and proteasomal degradation regulates various cellular pathways, and the discovery that CPT induced rapid proteasomal degradation of topoI is the primary mechanism of CPT resistance was novel and compelling. CPTs are used extensively to treat various solid tumors like colorectal, gastric, pancreatic, ovarian and small cell lung cancer. The response rate is low and the classical mechanisms of drug resistance are yet to be validated. Remarkably, CPT resistant cells degrade topoI rapidly by UPP and recently we’ve published the molecular determinants of this pathway. To further understand the UPP mediated CPT resistance mechanism we used targeted proteasome prohibition by ixazomib (MLN9708) to stabilize topoI and determine its impact on CPT resistance. CPT resistant and sensitive cancer lines were both treated with ixazomib in combination with CPT. The CPT induced rate of topoI degradation, and its stabilization by ixazomib, was visualized and estimated by immunohistochemistry, immunofluorescence and immunoblotting assays, MTT and subG1 assays provided the drug sensitivity. Our results demonstrate that cells that degrade topoI rapidly are very resistant to CPT, and ixazomib significantly inhibits CPT induced topoI degradation. Notably, inhibition of proteasomal degradation by ixazomib overcomes the drug resistance and sensitizes the cells for CPTs.

Keywords

Topoisomerase I; irinotecan; camptothecin; ubiquitination; proteasomal degradation; drug resistance

Subject

Medicine and Pharmacology, Immunology and Allergy

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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