The underlying molecular mechanisms of resistance to
cisplatin-based systemic
chemotherapy in
bladder cancer patients remain to be elucidated, while the link between
androgen receptor (AR) activity and chemosensitivity in urothelial
cancer has been implicated. Our
DNA microarray analysis in control vs. AR knockdown
bladder cancer lines identified GULP1 as a potential target of AR signaling. We herein determined the relationship between AR activity and GULP1 expression in
bladder cancer cells and then assessed the functional role of GULP1 in
cisplatin sensitivity.
Androgen treatment in AR-positive cells or AR overexpression in AR-negative cells considerably reduced the levels of GULP1 expression.
Chromatin immunoprecipitation further showed direct interaction of AR with the promoter region of GULP1. Meanwhile, GULP1 knockdown sublines were significantly more resistant to
cisplatin treatment compared with respective controls. GULP1 knockdown also resulted in a significant decrease in apoptosis, as well as a significant increase in G2/M phases, when treated with
cisplatin. In addition, GULP1 was immunoreactive in 74% of muscle-invasive
bladder cancers from patients who had subsequently undergone
neoadjuvant chemotherapy, including 53% of responders showing moderate (2+)/strong (3+) expression vs. 23% of non-responders showing 2+/3+ expression (P = 0.044). These findings indicate that GULP1 represents a key downstream effector of AR signaling in enhancing sensitivity to
cisplatin treatment.