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

Publisher: Springer Country of Publication: Switzerland NLM ID: 9705402 Publication Model: Electronic Cited Medium: Internet ISSN: 1420-9071 (Electronic) Linking ISSN: 1420682X NLM ISO Abbreviation: Cell Mol Life Sci Subsets: MEDLINE

Publication: Basel : Springer
Original Publication: Basel ; Boston : Birkhauser, c1997-

Tubulin*/genetics ; Ovarian Neoplasms*/drug therapy ; Ovarian Neoplasms*/genetics; Humans ; Female ; Carboplatin/pharmacology ; Carboplatin/therapeutic use ; Up-Regulation ; Transcriptional Activation

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.
(© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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DOC 59 Austria FWF_ Austrian Science Fund FWF; IP-2016-06-1036 Hrvatska Zaklada za Znanost; DOK-2018-01-8086 Hrvatska Zaklada za Znanost

Keywords: Cancer drug resistance; Cellular trafficking; Microtubules; Ovarian cancer therapy; Pt-drugs accumulation

BG3F62OND5 (Carboplatin)
0 (Tubulin)

Date Created: 20230917 Date Completed: 20230919 Latest Revision: 20240626

20240626

PMC11071939

10.1007/s00018-023-04943-0

37718345