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

Pernar Kovač, Margareta; Tadić, Vanja; Kralj, Juran; Duran, George E; Stefanelli, Alessia; Stupin Polančac, Darija; Dabelić, Sanja; Bačić, Niko; Tomicic, Maja T.; Heffeter, Petra; Sikic, Branimir I; Brozović, Anamaria (2023) Carboplatin-induced upregulation of pan β-tubulin and class III β-tubulin is implicated in acquired resistance and cross-resistance of ovarian cancer. Cellular and Molecular Life Sciences, 17 (80). p. 294. ISSN 1420-9071

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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.

Item Type:	Article
Uncontrolled Keywords:	Cancer drug resistance; Cellular trafficking; Microtubules; Ovarian cancer therapy; Pt-drugs accumulation
Subjects:	NATURAL SCIENCES NATURAL SCIENCES > Biology NATURAL SCIENCES > Biology > Biochemistry and Molecular Biology
Divisions:	Division of Molecular Biology
Projects:	Project title Project leader Project code Project type Određivanje ključnih molekula epitelno-mezenhimalne tranzicije kao mogućih ciljeva za terapiju raka jajnika Anamaria Brozovic IP-2016–06-1036 Znanstveno-istraživački projekti
Depositing User:	Anamaria Brozović
Date Deposited:	09 Jan 2024 11:33
URI:	http://fulir.irb.hr/id/eprint/8320
DOI:	10.1007/s00018-023-04943-0

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