FOXO1 inactivation induces cisplatin resistance in bladder cancer

Abstract

We found that FOXO1‐shRNA sublines or FOXO1‐positive cells co–treated with a FOXO1 inhibitor were significantly more resistant to cisplatin treatment at pharmacological concentrations, compared with respective control sublines or those with mock treatment. Western blot demonstrated considerable increases in the expression levels of a phosphorylated inactive form of FOXO1 (p‐FOXO1) in cisplatin‐resistant sublines established by long‐term culture with low/increasing doses of cisplatin, compared with respective controls. Immunohistochemistry in surgical specimens from patients with muscle‐invasive bladder cancer undergoing cisplatin‐based neoadjuvant therapy further showed a strong trend to associate between p‐FOXO1 positivity and unfavorable response to chemotherapy.

The Role of Estrogen Receptors in Urothelial Cancer

“…In these cisplatin-resistant cells, E2 treatment was also found to increase the expression and activity of b-catenin known to contribute to cisplatin resistance. We additionally showed that FOXO1, which could be inactivated via the ERb pathway as described above (69), was also inactivated in cisplatin-resistant bladder cancer cells and that FOXO1 knockdown or inhibitor treatment significantly induced resistance to cisplatin in bladder cancer cells (83). Meanwhile, in transurethral resection specimens from those, especially female patients, who subsequently received cisplatin-based neoadjuvant chemotherapy prior to radical cystectomy, loss of ERb immunoreactivity was strongly associated with favorable chemoresponse (35).…”

“…Further clinical studies are thus required for determining the actual benefit of anti-estrogen (or estrogen) treatment in patients with urothelial cancer. In particular, more convincing preclinical data exist to predict enhanced sensitivity to conventional non-surgical therapy against bladder cancer via anti-estrogens ( 35 , 50 , 70 , 80 , 81 , 83 ). In these studies, the role of ERα/ERβ expression in clinical samples, as a predictor of therapeutic response, may also need to be explored.…”

Androgen Receptor Signaling Induces Cisplatin Resistance via Down-Regulating GULP1 Expression in Bladder Cancer

“…Although resistance to CDDP-based chemotherapy is not uncommonly seen in patients with urothelial cancer, its underlying mechanisms are not fully understood. Meanwhile, AR activation in bladder cancer cells has been implicated to be associated with chemoresistance [ 12 , 13 , 14 , 15 , 21 , 22 , 23 , 24 ]. In the present study, we further investigated the role of GULP1, as a downstream target of AR, in CDDP resistance, using bladder cancer cell lines as well as surgical specimens.…”

Sex Hormone Receptor Signaling in Bladder Cancer: A Potential Target for Enhancing the Efficacy of Conventional Non-Surgical Therapy

“…As aforementioned, both androgen and estrogen could inactivate a tumor suppressor FOXO1 via the AR and ERβ pathways, respectively, in bladder cancer cells [ 32 ]. We further found that silencing of FOXO1 or treatment with an FOXO1 inhibitor in bladder cancer cells resulted in the reduction of sensitivity to cisplatin [ 77 ]. The expression of an inactivated form phospho-FOXO1 was considerably up-regulated in cisplatin-resistant cells, compared with control cells, and phospho-FOXO1 expression in transurethral resection specimens from patients undergoing cisplatin-based neoadjuvant chemotherapy was more often seen in non-responders (67.9%) than in responders (38.9%) [ 77 ].…”

“…We further found that silencing of FOXO1 or treatment with an FOXO1 inhibitor in bladder cancer cells resulted in the reduction of sensitivity to cisplatin [ 77 ]. The expression of an inactivated form phospho-FOXO1 was considerably up-regulated in cisplatin-resistant cells, compared with control cells, and phospho-FOXO1 expression in transurethral resection specimens from patients undergoing cisplatin-based neoadjuvant chemotherapy was more often seen in non-responders (67.9%) than in responders (38.9%) [ 77 ]. FOXO1 inactivation could thus be an underlying mechanism for chemoresistance in bladder cancer induced by AR and/or ERβ signals.…”