Inhibition of LOXL2 Enhances the Radiosensitivity of Castration-Resistant Prostate Cancer Cells Associated with the Reversal of the EMT Process

Introduction. Radiotherapy is the mainstay in the treatment of prostate cancer. However, significant radioresistance of castration-resistant prostate cancer (CRPC) cells constitutes a main obstacle in the treatment of this disease. By using bioinformatic data mining methods, LOXL2 was found to be upregulated in both androgen-independent prostate cancer cell lines and radioresistant tumor samples collected from patients with prostate cancer. We speculate that LOXL2 may play an important role in the radioresistance of CRPC cells. Methods. The effect of LOXL2 knockdown on the radiosensitivity of androgen-independent prostate cancer cells lines was measured by the clonogenic assay and xenograft tumor experiments under in vitro and in vivo conditions, respectively. In studies on the mechanism, we focused on the EMT phenotype changes and cell apoptosis changes induced by LOXL2 knockdown in DU145 cells. The protein levels of three EMT biomarkers, namely, E-cadherin, vimentin, and N-cadherin, were measured by western blotting and immunohistochemical staining. Cell apoptosis after irradiation was measured by flow cytometry and caspase-3 activity assay. Salvage experiment was also conducted to confirm the possible role of EMT in the radiosensitization effect of LOXL2 knockdown in CRPC cells. Results. LOXL2 knockdown in CRPC cells enhanced cellular radiosensitivity under both in vitro and in vivo conditions. A significant reversal of EMT was observed in LOXL2-silenced DU145 cells. Cell apoptosis after irradiation was significantly enhanced by LOXL2 knockdown in DU145 cells. Results from the salvage experiment confirmed the key role of EMT process reversal in the radiosensitization effect of LOXL2 knockdown in DU145 cells. Conclusions. LOXL2 plays an important role in the development of cellular radioresistance in CRPC cells. Targeting LOXL2 may be a rational avenue to overcome radioresistance in CRPC cells. A LOXL2-targeting strategy for CRPC treatment warrants detailed investigation in the future.

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Overexpression of SOCS3 mediated by adenovirus vector in mouse and human castration-resistant prostate cancer cells increases the sensitivity to NK cells in vitro and in vivo

Cancer Gene Therapy ◽

10.1038/s41417-018-0075-5 ◽

2019 ◽

Vol 26 (11-12) ◽

pp. 388-399 ◽

Cited By ~ 2

Author(s):

Tomomi Yoneda ◽

Naoto Kunimura ◽

Koichi Kitagawa ◽

Yuka Fukui ◽

Hiroki Saito ◽

...

Keyword(s):

Prostate Cancer ◽

Nk Cells ◽

Cancer Cells ◽

Adenovirus Vector ◽

Castration Resistant Prostate Cancer ◽

Prostate Cancer Cells ◽

Castration Resistant

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Abstract A76: MDV3100, a novel androgen receptor signaling inhibitor, promotes cell apoptosis and tumor regression in both in vitro and in vivo models of castration-resistant prostate cancer.

10.1158/1535-7163.targ-11-a76 ◽

2011 ◽

Author(s):

Sebastian Bernales ◽

Javier Guerrero ◽

Francisco Gomez ◽

Ivan E. Alfaro ◽

Kanako Iguchi ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cell Apoptosis ◽

Tumor Regression ◽

Castration Resistant Prostate Cancer ◽

In Vivo Models ◽

Androgen Receptor Signaling ◽

Castration Resistant

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S100A3 Suppression Inhibits In Vitro and In Vivo Tumor Growth and Invasion of Human Castration-resistant Prostate Cancer Cells

Urology ◽

10.1016/j.urology.2014.09.018 ◽

2015 ◽

Vol 85 (1) ◽

pp. 273.e9-273.e15 ◽

Cited By ~ 13

Author(s):

Minyong Kang ◽

Hye Sun Lee ◽

Young Ju Lee ◽

Woo Suk Choi ◽

Yong Hyun Park ◽

...

Keyword(s):

Prostate Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Castration Resistant Prostate Cancer ◽

Prostate Cancer Cells ◽

Castration Resistant ◽

Tumor Growth And Invasion

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HOTAIR-mediated reciprocal regulation of EZH2 and DNMT1 contribute to polyphyllin I-inhibited growth of castration-resistant prostate cancer cells in vitro and in vivo

Biochimica et Biophysica Acta (BBA) - General Subjects ◽

10.1016/j.bbagen.2017.12.001 ◽

2018 ◽

Vol 1862 (3) ◽

pp. 589-599 ◽

Cited By ~ 13

Author(s):

SongTao Xiang ◽

PeiLiang Zou ◽

Qing Tang ◽

Fang Zheng ◽

JingJing Wu ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Castration Resistant Prostate Cancer ◽

Prostate Cancer Cells ◽

Reciprocal Regulation ◽

Castration Resistant

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Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Calcium Signal Transducer 2 (TACSTD2)

Cancers ◽

10.3390/cancers13163959 ◽

2021 ◽

Vol 13 (16) ◽

pp. 3959

Author(s):

Oluwaseun Adebayo Bamodu ◽

Yuan-Hung Wang ◽

Chen-Hsun Ho ◽

Su-Wei Hu ◽

Chia-Da Lin ◽

...

Keyword(s):

Prostate Cancer ◽

Disease Progression ◽

Therapy Resistance ◽

Calcium Signal ◽

Signal Transducer ◽

Castration Resistance ◽

Castration Resistant

Background: prostate cancer (PCa) is a principal cause of cancer-related morbidity and mortality. Castration resistance and metastasis are clinical challenges and continue to impede therapeutic success, despite diagnostic and therapeutic advances. There are reports of the oncogenic activity of genetic suppressor element (GSE)1 in breast and gastric cancers; however, its role in therapy resistance, metastasis, and susceptibility to disease recurrence in PCa patients remains unclear. Objective: this study investigated the role of aberrantly expressed GSE1 in the metastasis, therapy resistance, relapse, and poor prognosis of advanced PCa. Methods: we used a large cohort of multi-omics data and in vitro, ex vivo, and in vivo assays to investigate the potential effect of altered GSE1 expression on advanced/castration-resistant PCa (CRPC) treatment responses, disease progression, and prognosis. Results: using a multi-cohort approach, we showed that GSE1 is upregulated in PCa, while tumor-associated calcium signal transducer 2 (TACSTD2) is downregulated. Moreover, the direct, but inverse, correlation interaction between GSE1 and TACSTD2 drives metastatic disease, castration resistance, and disease progression and modulates the clinical and immune statuses of patients with PCa. Patients with GSE1highTACSTD2low expression are more prone to recurrence and disease-specific death than their GSE1lowTACSTD2high counterparts. Interestingly, we found that the GSE1–TACSTD2 expression profile is associated with the therapy responses and clinical outcomes in patients with PCa, especially those with metastatic/recurrent disease. Furthermore, we demonstrate that the shRNA-mediated targeting of GSE1 (shGSE1) significantly inhibits cell proliferation and attenuates cell migration and tumorsphere formation in metastatic PC3 and DU145 cell lines, with an associated suppression of VIM, SNAI2, and BCL2 and the concomitant upregulation of TACSTD2 and BAX. Moreover, shGSE1 enhances sensitivity to the antiandrogens abiraterone and enzalutamide in vitro and in vivo. Conclusion: these data provide preclinical evidence of the oncogenic role of dysregulated GSE1–TACSTD2 signaling and show that the molecular or pharmacological targeting of GSE1 is a workable therapeutic strategy for inhibiting androgen-driven oncogenic signals, re-sensitizing CRPC to treatment, and repressing the metastatic/recurrent phenotypes of patients with PCa.

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MicroRNA-1205 Regulation of FRYL in Prostate Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.647485 ◽

2021 ◽

Vol 9 ◽

Author(s):

Michelle Naidoo ◽

Fayola Levine ◽

Tamara Gillot ◽

Akintunde T. Orunmuyi ◽

E. Oluwabunmi Olapade-Olaopa ◽

...

Keyword(s):

Prostate Cancer ◽

Neuroendocrine Differentiation ◽

Castration Resistant Prostate Cancer ◽

Chromosomal Locus ◽

Protein Coding ◽

Castration Resistant ◽

Dendritic Branching ◽

Very High

High mortality rates of prostate cancer (PCa) are associated with metastatic castration-resistant prostate cancer (CRPC) due to the maintenance of androgen receptor (AR) signaling despite androgen deprivation therapies (ADTs). The 8q24 chromosomal locus is a region of very high PCa susceptibility that carries genetic variants associated with high risk of PCa incidence. This region also carries frequent amplifications of the PVT1 gene, a non-protein coding gene that encodes a cluster of microRNAs including, microRNA-1205 (miR-1205), which are largely understudied. Herein, we demonstrate that miR-1205 is underexpressed in PCa cells and tissues and suppresses CRPC tumors in vivo. To characterize the molecular pathway, we identified and validated fry-like (FRYL) as a direct molecular target of miR-1205 and observed its overexpression in PCa cells and tissues. FRYL is predicted to regulate dendritic branching, which led to the investigation of FRYL in neuroendocrine PCa (NEPC). Resistance toward ADT leads to the progression of treatment related NEPC often characterized by PCa neuroendocrine differentiation (NED), however, this mechanism is poorly understood. Underexpression of miR-1205 is observed when NED is induced in vitro and inhibition of miR-1205 leads to increased expression of NED markers. However, while FRYL is overexpressed during NED, FRYL knockdown did not reduce NED, therefore revealing that miR-1205 induces NED independently of FRYL.

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Crosstalk Between Nuclear MET and SOX9/β-Catenin Correlates with Castration-Resistant Prostate Cancer

Molecular Endocrinology ◽

10.1210/me.2014-1078 ◽

2014 ◽

Vol 28 (10) ◽

pp. 1629-1639 ◽

Cited By ~ 26

Author(s):

Yingqiu Xie ◽

Wenfu Lu ◽

Shenji Liu ◽

Qing Yang ◽

Brett S. Carver ◽

...

Keyword(s):

Prostate Cancer ◽

Combined Treatment ◽

Castration Resistant Prostate Cancer ◽

Ablation Therapy ◽

Androgen Ablation ◽

Castration Resistant ◽

Activate Cell ◽

Androgen Ablation Therapy

Castration-resistant prostate cancer (PCa) (CRPC) is relapse after various forms of androgen ablation therapy and causes a major mortality in PCa patients, yet the mechanism remains poorly understood. Here, we report the nuclear form of mesenchymal epithelial transition factor (nMET) is essential for CRPC. Specifically, nMET is remarkably increased in human CRPC samples compared with naïve samples. Androgen deprivation induces endogenous nMET and promotes cell proliferation and stem-like cell self-renewal in androgen-nonresponsive PCa cells. Mechanistically, nMET activates SRY (sex determining region Y)-box9, β-catenin, and Nanog homeobox and promotes sphere formation in the absence of androgen stimulus. Combined treatment of MET and β-catenin enhances the inhibition of PCa cell growth. Importantly, MET accumulation is detected in nucleus of recurrent prostate tumors of castrated Pten/Trp53 null mice, whereas MET elevation is predominantly found in membrane of naïve tumors. Our findings reveal for the first time an essential role of nMET association with SOX9/β-catenin in CRPC in vitro and in vivo, highlighting that nuclear RTK activate cell reprogramming to drive recurrence, and targeting nMET would be a new avenue to treat recurrent cancers.

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Arginine vasopressin receptor 1a is a therapeutic target for castration-resistant prostate cancer

Science Translational Medicine ◽

10.1126/scitranslmed.aaw4636 ◽

2019 ◽

Vol 11 (498) ◽

pp. eaaw4636 ◽

Cited By ~ 4

Author(s):

Ning Zhao ◽

Stephanie O. Peacock ◽

Chen Hao Lo ◽

Laine M. Heidman ◽

Meghan A. Rice ◽

...

Keyword(s):

Prostate Cancer ◽

Arginine Vasopressin ◽

Ectopic Expression ◽

Vasopressin Receptor ◽

Castration Resistant Prostate Cancer ◽

Castration Resistance ◽

Castration Resistant ◽

Promising Therapeutic Approach

Castration-resistant prostate cancer (CRPC) recurs after androgen deprivation therapy (ADT) and is incurable. Reactivation of androgen receptor (AR) signaling in the low androgen environment of ADT drives CRPC. This AR activity occurs through a variety of mechanisms, including up-regulation of AR coactivators such as VAV3 and expression of constitutively active AR variants such as the clinically relevant AR-V7. AR-V7 lacks a ligand-binding domain and is linked to poor prognosis. We previously showed that VAV3 enhances AR-V7 activity to drive CRPC progression. Gene expression profiling after depletion of either VAV3 or AR-V7 in CRPC cells revealed arginine vasopressin receptor 1a (AVPR1A) as the most commonly down-regulated gene, indicating that this G protein–coupled receptor may be critical for CRPC. Analysis of publicly available human PC datasets showed thatAVPR1Ahas a higher copy number and increased amounts of mRNA in advanced PC. Depletion of AVPR1A in CRPC cells resulted in decreased cell proliferation and reduced cyclin A. In contrast, androgen-dependent PC, AR-negative PC, or nontumorigenic prostate epithelial cells, which have undetectableAVPR1AmRNA, were minimally affected by AVPR1A depletion. Ectopic expression of AVPR1A in androgen-dependent PC cells conferred castration resistance in vitro and in vivo. Furthermore, treatment of CRPC cells with the AVPR1A ligand, arginine vasopressin (AVP), activated ERK and CREB, known promoters of PC progression. A clinically safe and selective AVPR1A antagonist, relcovaptan, prevented CRPC emergence and decreased CRPC orthotopic and bone metastatic growth in mouse models. Based on these preclinical findings, repurposing AVPR1A antagonists is a promising therapeutic approach for CRPC.

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