Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Microtubule Dynamics Deregulation Induces Apoptosis in Human Urothelial Bladder Cancer Cells via a p53-independent Pathway

Yiannis Drosos
* ORCID logo ,
Eumorphia G. Konstantakou
ORCID logo ,
Aggeliki-Stefania Bassogianni
,
Konstantinos-Stylianos Nikolakopoulos
ORCID logo ,
Dimitra G. Koumoundourou
,
Sophia P. Markaki
ORCID logo ,
Ourania E. Tsitsilonis
ORCID logo ,
Gerassimos E. Voutsinas
,
Dimitrios Valakos
ORCID logo ,
Ema Anastasiadou
,
Dimitris Thanos
,
Athanassios D. Velentzas
ORCID logo ,
Dimitrios J. Stravopodis
* ORCID logo
Version 1 : Received: 20 June 2023 / Approved: 21 June 2023 / Online: 21 June 2023 (03:50:47 CEST)

A peer-reviewed article of this Preprint also exists.

Drosos, Y.; Konstantakou, E.G.; Bassogianni, A.-S.; Nikolakopoulos, K.-S.; Koumoundourou, D.G.; Markaki, S.P.; Tsitsilonis, O.E.; Voutsinas, G.E.; Valakos, D.; Anastasiadou, E.; Thanos, D.; Velentzas, A.D.; Stravopodis, D.J. Microtubule Dynamics Deregulation Induces Apoptosis in Human Urothelial Bladder Cancer Cells via a p53-Independent Pathway. Cancers 2023, 15, 3730. Drosos, Y.; Konstantakou, E.G.; Bassogianni, A.-S.; Nikolakopoulos, K.-S.; Koumoundourou, D.G.; Markaki, S.P.; Tsitsilonis, O.E.; Voutsinas, G.E.; Valakos, D.; Anastasiadou, E.; Thanos, D.; Velentzas, A.D.; Stravopodis, D.J. Microtubule Dynamics Deregulation Induces Apoptosis in Human Urothelial Bladder Cancer Cells via a p53-Independent Pathway. Cancers 2023, 15, 3730.

Abstract

Bladder cancer (BLCA) is the sixth most common type of cancer and has a dismal prognosis if diagnosed late. To identify treatment options for BLCA, we systematically evaluated data from the Broad Institute DepMap project. We found that urothelial BLCA cell lines are among the most sensitive to microtubule assembly inhibition by paclitaxel treatment. Strikingly, we unveiled that the top dependencies in BLCA cell lines include genes encoding proteins involved in microtubule assembly, thus highlighting the importance of microtubule network dynamics as a major vulnerability in human BLCA. In cancers, such as ovarian and breast, where paclitaxel is the golden standard of care, resistance to paclitaxel treatment has been linked to p53-inactivating mutations. To study the response of BLCA to microtubule assembly inhibition and its mechanistic link with the mutational status of p53 protein, we treated a collection of BLCA cell lines with a dose range of paclitaxel and performed a detailed characterization of the response. We herein discovered that BLCA cell lines are significantly sensitive to low concentrations of paclitaxel, independently of their p53 status. Paclitaxel induced a G2/M cell cycle arrest and growth inhibition, followed by robust activation of apoptosis. Most importantly, we revealed that paclitaxel triggered a robust DNA-damage response and apoptosis program without activating the p53 pathway. Integration of transcriptomics, epigenetic and dependency data demonstrated that the response of BLCA to paclitaxel is independent of p53 mutational signatures, but strongly depends on the expression of DNA-repair genes. Our work highlights urothelial BLCA as an exceptional candidate for paclitaxel treatment and paves the way for the rational use of a combination of paclitaxel and DNA-repair inhibitors as an effective, novel therapeutic strategy.

Keywords

Apoptosis; Bladder; Cancer; Microtubule; p53; Paclitaxel; Urothelium

Subject

Medicine and Pharmacology, Oncology and Oncogenics

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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