scholarly journals Circular RNA cir-ITCH Is a Potential Therapeutic Target for the Treatment of Castration-Resistant Prostate Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Shoubin Li ◽  
Chunhong Yu ◽  
Yunxia Zhang ◽  
Junjiang Liu ◽  
Yi Jia ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cell Lines ◽  
Therapeutic Target ◽  
Critical Role ◽  
Circular Rna ◽  
Migration And Invasion ◽  
Castration Resistant Prostate Cancer ◽  
Normal Prostate ◽  
Castration Resistant

cir-ITCH, a well-known tumor-suppressive circular RNA, plays a critical role in different cancers. However, its expression and functional role in prostate cancer (PCa) are unclear. Herein, we explored the potential mechanism and tumor-inhibiting role of cir-ITCH in PCa. Using reverse transcriptase polymerase chain reaction assay, we analyzed the expression of cir-ITCH in PCa and paired adjacent nontumor tissue samples resected during surgical operation, as well as in two cell lines of human PCa (LNCaP and PC-3) and the immortalized normal prostate epithelial cell line (RWPE-1). Cell viability and migration of PCa cell lines were evaluated using CCK-8 and wound-healing assays. Expression of key proteins of the Wnt/β-catenin and PI3K/AKT/mTOR pathways was detected using western blotting. We found that cir-ITCH expression was typically downregulated in the tissues and cell lines of PCa compared to that in the peritumoral tissue and in RWPE-1 cells, respectively. The results showed that cir-ITCH overexpression significantly inhibits the proliferation, migration, and invasion of human PCa cells and that reciprocal inhibition of expression occurred between cir-ITCH and miR-17. Proteins in the Wnt/β-catenin and PI3K/AKT/mTOR pathways were downregulated by overexpression of cir-ITCH both in androgen receptor-positive LNCaP cells and androgen receptor-negative PC-3 cells. Taken together, these data demonstrated that cir-ITCH plays a tumor-suppressive role in human PCa cells, partly through the Wnt/β-catenin and PI3K/AKT/mTOR pathways. Thus, cir-ITCH may serve as a novel therapeutic target for the treatment of PCa, especially castration-resistant prostate cancer.

scholarly journals Interplay Between SOX9, Wnt/β-Catenin and Androgen Receptor Signaling in Castration-Resistant Prostate Cancer

2019 ◽  
Vol 20 (9) ◽  
pp. 2066 ◽  
Author(s):  
Namrata Khurana ◽  
Suresh C. Sikka
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Signaling Pathways ◽  
Critical Role ◽  
Castration Resistant Prostate Cancer ◽  
Form Complex ◽  
Androgen Receptor Signaling ◽  
Castration Resistant ◽  
Signaling Axis

Androgen receptor (AR) signaling plays a key role not only in the initiation of prostate cancer (PCa) but also in its transition to aggressive and invasive castration-resistant prostate cancer (CRPC). However, the crosstalk of AR with other signaling pathways contributes significantly to the emergence and growth of CRPC. Wnt/β-catenin signaling facilitates ductal morphogenesis in fetal prostate and its anomalous expression has been linked with PCa. β-catenin has also been reported to form complex with AR and thus augment AR signaling in PCa. The transcription factor SOX9 has been shown to be the driving force of aggressive and invasive PCa cells and regulate AR expression in PCa cells. Furthermore, SOX9 has also been shown to propel PCa by the reactivation of Wnt/β-catenin signaling. In this review, we discuss the critical role of SOX9/AR/Wnt/β-catenin signaling axis in the development and progression of CRPC. The phytochemicals like sulforaphane and curcumin that can concurrently target SOX9, AR and Wnt/β-catenin signaling pathways in PCa may thus be beneficial in the chemoprevention of PCa.

A circulating tumor cell specific RNA assay for assessment of androgen receptor signaling inhibitor sensitivity in metastatic castration-resistant prostate cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5059-5059
Author(s):  
Pai-Chi Teng ◽  
Yu Jen Jan ◽  
Junhee Yoon ◽  
Pin-Jung Chen ◽  
Jie-Fu Chen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Drug Resistance ◽  
Androgen Receptor ◽  
Tumor Cell ◽  
Cell Lines ◽  
Circulating Tumor Cell ◽  
Z Score ◽  
Castration Resistant Prostate Cancer ◽  
Androgen Receptor Signaling ◽  
Castration Resistant

5059 Background: Our objective is to develop a circulating tumor cell (CTC)-RNA assay for characterizing clinically relevant RNA signatures for the assessment of androgen receptor signaling inhibitors (ARSIs) sensitivity in metastatic castration-resistant prostate cancer (mCRPC) patients. Methods: We developed NanoVelcro CTC-RNA Assay by combining Thermoresponsive(TR)-NanoVelcro CTC purification system with NanoString nCounter platform for CTC purification and RNA analysis. Based on the well-validated, tissue-based Prostate Cancer Classification System (PCS), we selected the most aggressive and ARSI-resistant subtype- the PCS1, for CTC analysis. We applied a rigorous bioinformatic process to develop a CTC-PCS1 panel that is specific to PC CTCs. We validated NanoVelcro CTC-RNA Assay and CTC-PCS1 panel with PC cell lines to demonstrate sensitivity and specificity of the PCS1 Z score (the likelihood estimate of the PCS1 subtype) for identifying PCS1 subtype and ARSI resistance. We then selected 31 blood samples from 23 PC patients receiving ARSIs to test in our assay. The PCS1 Z score of each sample was computed and compared with ARSI treatment sensitivity. Results: We established a 16-gene CTC-PCS1 panel that consists of CTC-specific RNA signatures. The validation studies using PC cell lines showed that the assay can detect the RNA transcripts with high sensitivity and scalability in the range of 1-100 cells. We also showed that the genes in CTC-PCS1 panel is highly expressed in PC cells. We further demonstrated that the CTC-PCS1 panel is highly specific in identifying PCS1-like samples, and the high PCS1 Z score is associated with ARSI resistance. In patient bloods, ARSI-resistant samples (ARSI-R, n=14) had significantly higher PCS1 Z scores as compared with ARSI-sensitive samples (ARSI-S, n=17) (Rank-sum test, P=0.003). In 8 patients who were initially sensitive to ARSI (ARSI-S) and later developed resistance (ARSI-R), we found that the PCS1 Z score increased from the time of ARSI-S to the time of ARSI-R (Pairwise T-test, P=0.016). Conclusions: Using our new methodology, we developed a first-in-class CTC-RNA assay and demonstrated the feasibility of transforming clinically-relevant tissue-based RNA profiling into CTC tests. This approach allows for detecting RNA expression relevant to clinical drug resistance in a non-invasive fashion, which can facilitate patient-specific treatment selection and early detection of drug resistance- a goal in precision oncology.

scholarly journals HEXIM1 plays a critical role in the inhibition of the androgen receptor by anti-androgens

2014 ◽  
Vol 462 (2) ◽  
pp. 315-327 ◽  
Author(s):  
I-Ju Yeh ◽  
Kyung Song ◽  
Bryan M. Wittmann ◽  
Xiaodong Bai ◽  
David Danielpour ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Critical Role ◽  
Therapeutic Agents ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Inducible Protein

Our studies indicate that hexamethylene-bis-acetamide-inducible protein 1 (HEXIM1) is required for inhibition of the androgen receptor by anti-androgens. These studies have important implications in the development of therapeutic agents for castration-resistant prostate cancer.

Androgen receptor independent acquired mechanisms of resistance to enzalutamide in castration-resistant prostate cancer.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 129-129
Author(s):  
Russell Zelig Szmulewitz ◽  
Steve Kregel ◽  
Masis Isikbay ◽  
Yi Cai ◽  
James Lin Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cell Lines ◽  
Dna Sequences ◽  
Castration Resistant Prostate Cancer ◽  
Testosterone Levels ◽  
Castration Resistant ◽  
Stat Signaling

129 Background: Enzalutamide (MDV3100) is a second generation androgen receptor (AR) antagonist with potent activity in the treatment of castration resistant prostate cancer (CRPC). However, most patients develop resistance and progression of disease; thus there is a critical need to identify novel targetable pathways mechanistically linked to this resistance. Methods: A panel of four prostate cancer cell lines (LAPC-4, LNCaP, VCaP, and CWRR1) was created each with a different AR status that are resistant to MDV3100 by culturing cells long-term less than 6 months in the drug at pharmacologic levels. The MDV3100 resistant (MDV-R) lines were assayed for proliferation, viability, resistance to docetaxel, and tumor take of subcutaneous xenografts. AR expression and ligand binding domain (LBD) DNA sequences were analyzed. Gene expression microarray comparison of resistant and non-resistant parental cell lines was performed. Prostate-specific antigen (PSA) and testosterone levels were analyzed from conditioned media. Results: Cell lines demonstrated heterogeneous growth characteristics.In vivo studies depicted increased or unaltered tumor take and growth in castrate athymic mice. In some cell lines growth was increased in vitro when drug was withdrawn; yet this growth was inhibited by physiological testosterone levels, both in vitro and in vivo. MDV-R cells remained sensitive to docetaxel in vitro and had increased levels of ARmRNA. However, total AR protein levels were lower or unchanged than the parental lines, with evidence for increased truncated forms of AR. The AR LBD acquired no new mutations. Secreted PSA was lower in all but one MDV-R line. Gene expression analyses demonstrated strong upregulation of IGFBP3 in all MDV-R cells. Pathway analysis implicated increased IGF and JAK/STAT signaling whereas mammalian target of rapamycin (mTOR) signaling was decreased. Conclusions: Although AR-mediated pathways contribute to enzalutamide resistance, a broader approach across several cell lines suggests that there may be even a greater contribution from pleiotropic, non-AR mediated mechanisms. Such mechanisms may include IGF signaling, JAK/STAT signaling and modulation of mTOR.

scholarly journals Human heterochromatin protein 1 isoforms regulate androgen receptor signaling in prostate cancer

2013 ◽  
Vol 50 (3) ◽  
pp. 401-409 ◽  
Author(s):  
Momoe Itsumi ◽  
Masaki Shiota ◽  
Akira Yokomizo ◽  
Eiji Kashiwagi ◽  
Ario Takeuchi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Androgen Receptor ◽  
Cell Growth ◽  
Critical Role ◽  
Castration Resistant Prostate Cancer ◽  
Heterochromatin Protein 1 ◽  
Heterochromatin Protein ◽  
Castration Resistant ◽  
22Rv1 Cell

Androgen receptor (AR) signaling is critical for the tumorigenesis and development of prostate cancer, as well as the progression to castration-resistant prostate cancer. We previously showed that the heterochromatin protein 1 (HP1) β isoform plays a critical role in transactivation of AR signaling as an AR coactivator that promotes prostate cancer cell proliferation. However, the roles of other HP1 isoforms, HP1α and HP1γ, in AR expression and prostate cancer remain unclear. Here, we found that knockdown of HP1γ, but not HP1α, reduced AR expression and cell proliferation by inducing cell cycle arrest at G1 phase in LNCaP cells. Conversely, overexpression of full-length HP1α and its C-terminal deletion mutant increased AR expression and cell growth, whereas overexpression of HP1γ had no effect. Similarly, HP1α overexpression promoted 22Rv1 cell growth, whereas HP1γ knockdown reduced the proliferation of CxR cells, a castration-resistant LNCaP derivative. Taken together, HP1 isoforms distinctly augment AR signaling and cell growth in prostate cancer. Therefore, silencing of HP1β and HP1γ may be a promising therapeutic strategy for treatment of prostate cancer.

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