GULP1 as a Downstream Effector of the Estrogen Receptor-β Modulates Cisplatin Sensitivity in Bladder Cancer

Background/Aim: Precise molecular mechanisms underlying resistance to cisplatin-based chemotherapy remain unclear, while the activity of estrogen receptor-/3 (ER/3) has been suggested to be associated with chemosensitivity in urothelial cancer. We aimed to determine if GULP1, an adapter protein known to facilitate phagocytosis, could represent a downstream effector of ER/3 and thereby modulate cisplatin sensitivity in bladder cancer. Materials and Methods: GULP1 expression and cisplatin cytotoxicity were compared in bladder cancer lines. Immunohistochemistry was used to determine the expression of GULP1 and ER/3 in two sets of tissue microarray (TMA) consisting of transurethral resection specimens. Results: The levels of GULP1 expression were considerably higher in ER/3- knockdown sublines than in the respective control ER/3-positive sublines. Estradiol treatment reduced GULP1 expression in ERa-negative/ER/3-positive lines, which was restored by the anti- estrogen tamoxifen. Chromatin immunoprecipitation assay revealed the binding of ER/3 to the GULP1 promoter in bladder cancer cells. Moreover, GULP1 knockdown sublines were significantly more resistant to cisplatin treatment, but not to other chemotherapeutic agents, including gemcitabine, methotrexate, vinblastine, and doxorubicin. In the first set of TMA (n=129), the expression of ER/3 and GULP1 was inversely correlated (p=0.023), and ER/3(-)/GULP1(+) in 51 muscle- invasive tumors was associated with significantly lower risk of disease progression and cancer-specific mortality. Similarly, in the second set (n=43), patients with ER/3(-)/GULP1(+) muscle- invasive disease were significantly (p=0.021) more likely to be responders to cisplatin-based neoadjuvant chemotherapy before radical cystectomy. Conclusion: ER/3 activation was found to reduce the expression of GULP1 as a direct downstream target in bladder cancer cells, resulting in the induction of cisplatin resistance.