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Carboplatin-induced upregulation of pan β-tubulin and class III β-tubulin is implicated in acquired resistance and cross-resistance of ovarian cancer

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Abstract

Resistance to platinum- and taxane-based chemotherapy represents a major obstacle to long-term survival in ovarian cancer (OC) patients. Here, we studied the interplay between acquired carboplatin (CBP) resistance using two OC cell models, MES-OV CBP and SK-OV-3 CBP, and non-P-glycoprotein-mediated cross-resistance to paclitaxel (TAX) observed only in MES-OV CBP cells. Decreased platination, mesenchymal-like phenotype, and increased expression of α- and γ-tubulin were observed in both drug-resistant variants compared with parental cells. Both variants revealed increased protein expression of class III β-tubulin (TUBB3) but differences in TUBB3 branching and nuclear morphology. Transient silencing of TUBB3 sensitized MES-OV CBP cells to TAX, and surprisingly also to CBP. This phenomenon was not observed in the SK-OV-3 CBP variant, probably due to the compensation by other β-tubulin isotypes. Reduced TUBB3 levels in MES-OV CBP cells affected DNA repair protein trafficking and increased whole-cell platination level. Furthermore, TUBB3 depletion augmented therapeutic efficiency in additional OC cells, showing vice versa drug-resistant pattern, lacking β-tubulin isotype compensation visible at the level of total β-tubulin (TUBB) in vitro and ex vivo. In summary, the level of TUBB in OC should be considered together with TUBB3 in therapy response prediction.

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Acknowledgements

The authors would like to thank Prof. Dr. Gerhard Fritz (University of Düsseldorf, Germany) for critical reading of the manuscript, Prof. Dr. Christian R. Kowol (University of Vienna, Austria) for selfless help with the ICP-MS analysis at the moment when the RBI device was broken and Mag. Biotech. Marina Šutalo (Ruđer Bošković Institute) for technical assistance.

Funding

This publication is based on work financed by the Croatian Science Foundation (CSF, project numbers IP-2016–06-1036 and DOK-2018–01-8086) and upon work from COST Action 17104 STRATAGEM, supported by COST (European Cooperation in Science and Technology; www.cost.eu). Alessia Stefanelli is financed by the DOC funds program of the Austrian Science Fund (FWF).

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MPK, VT, and AB performed the experiments, with assistance from JK, GED, AS, DSP, SD, NB, MTC, and PH; MPK, VT, and AB analyzed and visualized the data; BIS provided resources for the beginning of the MES-OV CBP cell line establishment, GED and BIS were involved in language editing; AB conceptualized and supervised the project, acquired the funding, wrote original draft, and together with MPK and VT reviewed and edited the manuscript.

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Correspondence to Anamaria Brozovic.

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The Administrative Panel on Laboratory Animal Care (APLAC) of Stanford University, USA, approved all protocols in compliance with the Guide for the Care and Use of Laboratory Animals. The laboratory animal care program at Stanford is accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care (AAALAC International).

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Pernar Kovač, M., Tadić, V., Kralj, J. et al. Carboplatin-induced upregulation of pan β-tubulin and class III β-tubulin is implicated in acquired resistance and cross-resistance of ovarian cancer. Cell. Mol. Life Sci. 80, 294 (2023). https://doi.org/10.1007/s00018-023-04943-0

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