Abstract
Simple SummaryIt remains unclear why chemotherapy is often ineffective in patients with bladder cancer. Meanwhile, we previously reported that male sex hormones (i.e., androgens) could considerably reduce the efficacy of cisplatin, an anti-cancer drug used as the first-line treatment against advanced bladder cancer. The present study aimed to investigate how androgen receptor signaling, which is activated by binding of androgenic hormones, modulates sensitivity to cisplatin treatment in bladder cancer, using cell line models and surgical specimens. We found that the expression levels of the androgen receptor and a molecule (BXDC2) were inversely correlated and that loss of BXDC2 was associated with cisplatin resistance. We thus provide evidence to suggest an underlying molecular mechanism responsible for androgen receptor-induced chemoresistance in bladder cancer.Underlying mechanisms for resistance to cisplatin-based chemotherapy in bladder cancer patients are largely unknown, although androgen receptor (AR) activity, as well as extracellular signal-regulated kinase (ERK) signaling, has been indicated to correlate with chemosensitivity. We also previously showed ERK activation by androgen treatment in AR-positive bladder cancer cells. Because our DNA microarray analysis in control vs. AR-knockdown bladder cancer lines identified BXDC2 as a potential downstream target of AR, we herein assessed its functional role in cisplatin sensitivity, using bladder cancer lines and surgical specimens. BXDC2 protein expression was considerably downregulated in AR-positive or cisplatin-resistant cells. BXDC2-knockdown sublines were significantly more resistant to cisplatin, compared with respective controls. Without cisplatin treatment, BXDC2-knockdown resulted in significant increases/decreases in cell proliferation/apoptosis, respectively. An ERK activator was also found to reduce BXDC2 expression. Immunohistochemistry showed downregulation of BXDC2 expression in tumor (vs. non-neoplastic urothelium), higher grade/stage tumor (vs. lower grade/stage), and AR-positive tumor (vs. AR-negative). Patients with BXDC2-positive/AR-negative muscle-invasive bladder cancer had a significantly lower risk of disease-specific mortality, compared to those with a BXDC2-negative/AR-positive tumor. Additionally, in those undergoing cisplatin-based chemotherapy, BXDC2 positivity alone (p = 0.083) or together with AR negativity (p = 0.047) was associated with favorable response. We identified BXDC2 as a key molecule in enhancing cisplatin sensitivity. AR-ERK activation may thus be associated with chemoresistance via downregulating BXDC2 expression in bladder cancer.
Highlights
Urinary bladder cancer, mostly urothelial carcinoma, has been one of the most commonly diagnosed malignancies, especially in men [1,2]
We have demonstrated that activation of androgen receptor (AR) is associated with resistance to CDDP therapy in bladder cancer [9], while an increasing amount of evidence indicates an important role of AR in promoting both of two distinct steps/events, urothelial tumorigenesis and tumor progression [10]
We had recently employed DNA microarray analysis in control AR-positive UMUC3 versus a UMUC3 subline stably expressing AR-short hairpin RNA [12]. Of those expressed at absolutely high levels, several candidate genes were examined if their expression was upregulated in AR-knockdown cells and downregulated in CDDP-resistant cells
Summary
Mostly urothelial carcinoma, has been one of the most commonly diagnosed malignancies, especially in men [1,2]. Muscle-invasive bladder cancer is often associated with metastatic disease where the overall 5-year survival rate remains low (e.g., 5.5% [3]). Urothelial carcinoma occurs in the upper urinary tract and is often (e.g., 60% [4]) invasive at the time of initial diagnosis. While several immune checkpoint inhibitors have recently been approved for clinical use, cisplatin (CDDP)-based combination chemotherapy, such as “MVAC” (methotrexate (MTX)/vinblastine (VBL)/doxorubicin (DOX; Adriamycin)/CDDP), “GC” (gemcitabine (GEM)/CDDP), and “CMV” (CDDP/MTX/VBL), remains the mainstay of the treatment of locally advanced or metastatic urothelial carcinoma in a neoadjuvant or adjuvant setting [5,6]. The development of strategies for overcoming chemoresistance constitutes a goal with critical clinical implications
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