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

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.

Syngeneic model of carcinogen-induced tumor mimics basal/squamous, stromal-rich, and neuroendocrine molecular and immunological features of muscle-invasive bladder cancer

“…Based on retrospective clinical observations, the different molecular subtypes are prognostic of response (1,7,14,38). Recent studies have implicated a variety of pathways that contribute to chemoresistance including long noncoding RNAs (39,40), epigenetic pathways (41-47), miRNAs (48) and androgen signaling (44,(49)(50)(51)(52)(53). Based on previous observation that patients with stroma-rich subtype tumors have better prognosis as compared to those having the basal/squam subtype, the cisplatin response was evaluated in two BURP lines with molecular classifications of stromal-rich (BURP-16SR) and basal/squam (BURP-24BaSq).…”

Oridonin suppresses gastric cancer SGC‐7901 cell proliferation by targeting the TNF‐alpha/androgen receptor/TGF‐beta signalling pathway axis

“…AR is the androgen receptor, and AR signalling pathway is related to many hormone-dependent diseases such as prostate cancer, 49 breast cancer [50][51][52] and ovarian cancer, 53 as well as malignant tumours, for example gastric cancer, 54,55 lung cancer, 56,57 bladder cancer, 58,59 F I G U R E 8 Potential signalling pathway of oridonin on gastric cancer constructed in the present research.…”

Multi-Omics Analysis of Novel Signature for Immunotherapy Response and Tumor Microenvironment Regulation Patterns in Urothelial Cancer

“…Before proceeding further, we first demonstrated that the results of drug response estimation are reliable. Cisplatin is a common therapeutic agent for bladder cancer patients, and a recent study showed that high GULP1 expression enhanced the sensitivity of patients to cisplatin ( Teramoto et al, 2021 ). We divided the patients into high and low expression groups according to the expression level of GULP1.…”