TPD54 contributes to docetaxel resistance through modulation of P‑glycoprotein localization and activity in oral...

Tumor protein D52 (TPD52) family proteins are involved in the proliferation, survival and malignant progression of oral squamous cell carcinoma (OSCC). However, their roles in chemoresistance remain incompletely understood. The present study investigated the contribution of TPD52 family proteins to anticancer drug resistance, with particular emphasis on tumor protein D54 (TPD54). OSCC cells were treated with cisplatin, 5‑fluorouracil, or docetaxel (DTX), and the expression of TPD52 family members was examined. Gain‑ and loss‑of‑function analyses were performed to evaluate cell viability, apoptotic responses, cytochrome p450 (P450) and P‑glycoprotein (P‑gp) activities, protein expression, intracellular localization and membrane/cytosol distribution. Anticancer drug treatment increased the expression of TPD52, TPD53 and TPD54. Among these family members, TPD54 showed the strongest association with DTX resistance by attenuating the reduction in cell viability without affecting cell‑cycle progression. TPD54 overexpression attenuated DTX‑associated apoptotic responses and was associated with changes in apoptosis‑, ferroptosis‑, and autophagy‑related marker proteins. TPD54 expression had little effect on the activities of P450 3A4 or P450 1B1 but significantly increased P‑gp activity. Membrane/cytosol fractionation demonstrated increased membrane localization of endogenous P‑gp following TPD54 overexpression, whereas co‑immunoprecipitation and immunocytofluorescence analyses revealed an association and partial co‑localization between TPD54 and P‑gp. These findings suggest that TPD54 contributes to DTX resistance in OSCC cells through modulation of P‑gp localization and activity. The present study identifies TPD54 as a potential contributor to P‑gp‑associated chemoresistance and provides a basis for further investigation of the molecular mechanisms underlying multidrug resistance in OSCC.