Dataset Information

Tumor-derived OBP2A promotes prostate cancer castration resistance.

ABSTRACT: Androgen deprivation therapy (ADT) is a systemic therapy for advanced prostate cancer (PCa); although most patients initially respond to ADT, almost all cancers eventually develop castration-resistant PCa (CRPC). Currently, most research focuses on castration-resistant tumors, and the role of tumors in remission is almost completely ignored. Here, we report that odorant-binding protein (OBP2A) released from tumors in remission during ADT catches survival factors, such as CXCL15/IL8, to promote PCa cell androgen-independent growth and enhance the infiltration of myeloid-derived suppressor cells (MDSCs) into tumor microenvironment, leading to the emergence of castration resistance. OBP2A knockdown significantly inhibits CRPC and metastatic CRPC development and improves therapeutic efficacy of CTLA-4/PD-1 antibodies. Treatment with OBP2A-binding ligand α-pinene interrupts the function of OBP2A and suppresses CRPC development. Furthermore, α-pinene-conjugated doxorubicin/docetaxel can be specifically delivered to tumors, resulting in improved anticancer efficacy. Thus, our studies establish a novel concept for the emergence of PCa castration resistance and provide new therapeutic strategies for advanced PCa.

SUBMITTER: Jeong JH

PROVIDER: S-EPMC9789742 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Tumor-derived OBP2A promotes prostate cancer castration resistance.

Jeong Ji-Hak JH Zhong Shangwei S Li Fuzhuo F Huang Changhao C Chen Xueyan X Liu Qingqing Q Peng Shoujiao S Park HaJeung H Lee You Mie YM Dhillon Jasreman J Luo Jun-Li JL

The Journal of experimental medicine 20221222 3

Androgen deprivation therapy (ADT) is a systemic therapy for advanced prostate cancer (PCa); although most patients initially respond to ADT, almost all cancers eventually develop castration-resistant PCa (CRPC). Currently, most research focuses on castration-resistant tumors, and the role of tumors in remission is almost completely ignored. Here, we report that odorant-binding protein (OBP2A) released from tumors in remission during ADT catches survival factors, such as CXCL15/IL8, to promote P ...[more]

PMID: 36547668

Similar Datasets

Project description:Prostate cancer (CaP) progresses from prostatic intraepithelial neoplasia through locally invasive adenocarcinoma to castration-resistant metastatic carcinoma. Although radical prostatectomy, radiation and androgen ablation are effective therapies for androgen-dependent CaP, metastatic castration-resistant CaP is a major complication with high mortality. Androgens stimulate growth and survival of prostate epithelium and early CaP. Although most patients initially respond to androgen ablation, many develop castration-resistant CaP within 12-18 months. Despite extensive studies, the mechanisms underlying the emergence of castration-resistant CaP remain poorly understood and their elucidation is critical for developing improved therapies. Curiously, castration-resistant CaP remains androgen-receptor dependent, and potent androgen-receptor antagonists induce tumour regression in castrated mice. The role of inflammation in castration-resistant CaP has not been addressed, although it was reported that intrinsic NF-kappaB activation supports its growth. Inflammation is a localized protective reaction to injury or infection, but it also has a pathogenic role in many diseases, including cancer. Whereas acute inflammation is critical for host defence, chronic inflammation contributes to tumorigenesis and metastatic progression. The inflammation-responsive IkappaB kinase (IKK)-beta and its target NF-kappaB have important tumour-promoting functions within malignant cells and inflammatory cells. The latter, including macrophages and lymphocytes, are important elements of the tumour microenvironment, but the mechanisms underlying their recruitment remain obscure, although they are thought to depend on chemokine and cytokine production. We found that CaP progression is associated with inflammatory infiltration and activation of IKK-alpha, which stimulates metastasis by an NF-kappaB-independent, cell autonomous mechanism. Here we show that androgen ablation causes infiltration of regressing androgen-dependent tumours with leukocytes, including B cells, in which IKK-beta activation results in production of cytokines that activate IKK-alpha and STAT3 in CaP cells to enhance hormone-free survival.

Project description:BackgroundAdipose tissue has gained attention due to its potential paracrine role. Periprostatic adipose tissue surrounds the prostate and the prostatic urethra, and it is an essential player in prostate cancer progression. Since obesity is directly related to human tumor progression, and adipose tissue depots are one of the significant components of the tumor microenvironment, the molecular mediators of the communication between adipocytes and epithelial cells are in the spotlight. Although periprostatic white adipose tissue contributes to prostate cancer progression, brown adipose tissue (BAT), which has beneficial effects in metabolic pathologies, has been scarcely investigated concerning cancer progression. Given that adipose tissue is a target of androgen signaling, the actual role of androgen removal on the periprostatic adipose tissue was the aim of this work.MethodsSurgical castration of the transgenic adenocarcinoma of the mouse prostate (TRAMP) was employed. By histology examination and software analysis, WAT and BAT tissue was quantified. 3T3-like adipocytes were used to study the role of Casodex® in modifying adipocyte differentiation and to investigate the function of the secretome of adipocytes on the proliferation of androgen-dependent and independent prostate cancer cells. Finally, the role of cell communication was assayed by TRAMP-C1 xenograft implanted in the presence of 3T3-like adipocytes.ResultsAndrogen removal increases brown/beige adipose tissue in the fat immediately surrounding the prostate glands of TRAMP mice, concomitant with an adjustment of the metabolism. Castration increases body temperature, respiratory exchange rate, and energy expenditure. Also, in vitro, it is described that blocking androgen signaling by Casodex® increases the uncoupling protein 1 (UCP1) marker in 3T3-like adipocytes. Finally, the effect of brown/beige adipocyte secretome was studied on the proliferation of prostate cancer cells in vivo and in vitro. The secretome of brown/beige adipocytes reduces the proliferation of prostate cancer cells mediated partly by the secretion of extracellular vesicles.ConclusionsConsequently, we concluded that hampering androgen signaling plays a crucial role in the browning of the periprostatic adipose tissue. Also, the presence of brown adipocytes exhibits the opposite effect to that of white adipocytes in vitro regulating processes that govern the mechanisms of cell proliferation of prostate cancer cells. And finally, promoting the browning of adipose tissue in the periprostatic adipose tissue might be a way to handle prostate cancer cell progression. Video Abstract.

Project description:BackgroundProgression to castration resistance is the leading cause of death in prostate cancer patients. Long non-coding RNAs (lncRNAs) have recently become a focal point in the regulation of cancer development. However, few lncRNAs associated with castration-resistant prostate cancer (CRPC) have been reported.MethodsFirstly, we explore the CRPC associated lncRNAs by RNA sequencing and validated using quantitative polymerase chain reaction (qRT-PCR) and RNA fluorescence in situ hybridization (RNA-FISH). The clinical significance of FLJ was evaluated in a collected cancer cohort. Functional loss assays were performed to assess the effects of FLJ on CRPC cells both in vitro and in vivo. The regulatory mechanism of FLJ was investigated using immunohistochemistry (IHC), qRT-PCR, dual-luciferase reporter assays, and chromatin immunoprecipitation (ChIP) assays.ResultsFLJ is highly expressed in CRPC and is associated with higher stages and Gleason scores in prostate cancer. FLJ is strongly positively correlated with androgen receptor (AR), which acts as a transcription factor and directly binds to the FLJ promoter region to enhance its transcription. Knockdown of FLJ inhibits CRPC cell proliferation and increases sensitivity to castration and enzalutamide (ENZA) in vitro. Mechanistically, FLJ promotes castration resistance in prostate cancer cells by inhibiting AR nuclear import and cytoplasmic protein degradation, thereby activating the androgen-independent AR signaling pathway. Importantly, in vivo experiments showed that FLJ knockdown inhibited tumor growth and enhanced the therapeutic effect of ENZA.ConclusionsThis study identifies a novel regulatory mechanism by which lncRNA FLJ promotes CRPC progression. Sustained AR activation in CRPC acts as a transcription factor to upregulate FLJ expression. FLJ circumvents the traditional androgen-dependent survival mechanism by inhibiting AR nuclear entry and cytoplasmic protein degradation, thereby activating the AR signaling pathway. Targeting the FLJ-AR signaling axis may represent a novel therapeutic strategy for patients with castration-resistant prostate cancer.

Dataset Information

Tumor-derived OBP2A promotes prostate cancer castration resistance.

Publications

Tumor-derived OBP2A promotes prostate cancer castration resistance.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets