Abstract
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.
Highlights
Urinary bladder cancer, mostly urothelial carcinoma, has been one of the most commonly diagnosed malignancies, especially in men [1,2]
We recently employed DNA microarray analysis in control androgen receptor (AR)-positive UMUC3 versus a UMUC3 subline stably expressing AR-shRNA [16]. Of those expressed at absolutely high levels, several candidate genes were examined if their expression was upregulated in AR-knockdown cells and down-regulated in CDDP-resistant cells
We first examined the expression of GULP1 in four human bladder cancer lines that were known to be AR-negative (i.e., 5637, 647V) or AR-positive (i.e., UMUC3, TCCSUP) [19]
Summary
Mostly urothelial carcinoma, has been one of the most commonly diagnosed malignancies, especially in men [1,2]. There are two distinct forms of bladder cancer, non-muscle-invasive and muscle-invasive diseases, and the latter is often associated with metastatic disease where the overall 5-year survival rate remains low (i.e., 6.4% [3]). New therapeutic options, such as immune checkpoint blockade, have become available, cisplatin (CDDP)-based combination chemotherapy remains the first-line standard for locally advanced or metastatic urothelial carcinoma [5,6]. The response rate to a CDDP-containing regimen has been reported to be 40–60% in bladder cancer patients undergoing neoadjuvant chemotherapy followed by radical cystectomy [7,8]. The development of strategies for overcoming chemoresistance and predicting chemosensitivity constitutes a goal with critical clinical implications
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