Androgen receptor amplification is reflected in the transcriptional responses of Vertebral-Cancer of the Prostate cells

Makkonen, Harri; Kauhanen, Miia; Jääskeläinen, Tiina; Palvimo, Jorma J.

doi:10.1016/j.mce.2010.08.008

Cited by 45 publications

(44 citation statements)

References 44 publications

(36 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, in contrast, it was found that the androgen-free HCM also had an androgenic-like effect on the expression of a number of androgen responsive genes in both cell lines. This finding was contrary to the literature, as the HCM is deplete of androgens and therefore should not active an androgenic response (Makkonen et al, 2011). This androgen response varied between the two cell lines and as such the predicted potential mechanisms inducing that response are different.…”

Section: Hcm and Androgen Responsecontrasting

confidence: 93%

“…As predicted by previous research, the androgen treatment in both LNCaP and VCaP cell lines treated in RPMI with serum supplements (controls), induced a 'classic' androgen response, as documented in Table 4.3 & 4.14, with the predictable expression of certain well-characterized androgen regulated genes (Makkonen et al, 2011). However, in contrast, it was found that the androgen-free HCM also had an androgenic-like effect on the expression of a number of androgen responsive genes in both cell lines.…”

Section: Hcm and Androgen Responsesupporting

confidence: 68%

“…Additionally, VCaP cells have the ability to proliferate and survive androgen deprivation, making them ideal for analysing the transcriptomic response of ADT and occurrence of CRPC (Makkonen et al, 2011). This castration resistant nature of VCaP cell line was observed by researchers, finding enhanced levels of mRNA for PSA, AR, ERG and other genes enhancing certain metabolic functions such as lipid synthesis (Cai et al, 2011a).…”

Section: Pca Cell Linesmentioning

confidence: 99%

“…A potential limitation of the LNCaP cell line is that the AR of the cell is mutated and this mutation has been shown to effect steroid binding allowing non-androgen activation (Veldscholte et al, 1992). and there is a TMPRSS2-ETS-related gene (ERG) fusion which creates a more diverse model than using LNCaP cells alone (Makkonen, Kauhanen, Jääskeläinen, & Palvimo, 2011).…”

Section: Pca Cell Linesmentioning

confidence: 99%

“…(Makkonen et al, 2011). Based on these genes both the androgen-enriched RPMI and HCM treated LNCaP cells expressed an androgenic response profile (Table 4.3).…”

Section: Androgen Regulated Genes In Hcm Treated Lncap Cellsmentioning

confidence: 99%

See 4 more Smart Citations

Identification of response pathways of prostate cancer cell lines in Hans Clevers Media

Hutchinson¹

View full text Add to dashboard Cite

Section: Hcm and Androgen Responsecontrasting

confidence: 93%

Section: Hcm and Androgen Responsesupporting

confidence: 68%

Section: Pca Cell Linesmentioning

confidence: 99%

Section: Pca Cell Linesmentioning

confidence: 99%

“…(Makkonen et al, 2011). Based on these genes both the androgen-enriched RPMI and HCM treated LNCaP cells expressed an androgenic response profile (Table 4.3).…”

Section: Androgen Regulated Genes In Hcm Treated Lncap Cellsmentioning

confidence: 99%

See 3 more Smart Citations

Identification of response pathways of prostate cancer cell lines in Hans Clevers Media

Hutchinson¹

View full text Add to dashboard Cite

Modulation of the Androgen Receptor Axis

Mohler

Dalton

2021

Burger's Medicinal Chemistry and Drug Discovery

View full text Add to dashboard Cite

The androgen receptor (AR) mediates the endocrine functions of endogenous androgens like testosterone and exerts pleiotropic androgenic (male phenotype development, sexual function) and anabolic (growth and maintenance of musculoskeletal system) effects across most tissues. The AR‐axis, i.e. AR and its downstream effects, is extensively targeted to stimulate anabolism or treat prostatic diseases. Tissue‐selective, direct‐acting synthetic AR agonists are limited in scope by their inadequate separation of anabolic from untoward androgenic or virilizing effects and include FDA approved steroidal androgens (anabolic‐androgenic steroids) and investigational nonsteroidal selective AR modulators (SARMs). Gaining in popularity is testosterone replacement therapy in hypogonadal men. Antagonism of the AR‐axis is common in aging males with androgen‐dependent prostate hyperproliferation [prostate cancer or benign prostatic hyperplasia (BPH)]. Androgen ablation (indirect antagonism) and direct AR antagonism have been the mainstays of prostate cancer therapies for many decades including recent approvals. Indirect antagonists of the AR‐axis include gonadotropin‐releasing hormone agonists or antagonists (androgen‐deprivation therapy), which achieve systemic androgen and estrogen ablation for prostate or breast cancers as a monotherapy or sometimes in combination with steroidogenic enzyme (lyase) inhibitors. DHT‐dependent diseases are treated with 5α‐reductase to block intracrine production of DHT for male pattern baldness and BPH; whereas aromatase inhibitors block androgen metabolism to estrogen in breast cancer. Direct AR antagonists (antiandrogens) with improved potency and anti‐androgenic scope continue to be approved for prostate cancer. Research into innovative ways to directly or indirectly modulate the AR‐axis remains robust, suggesting new therapies will likely be introduced regularly for the foreseeable future.

show abstract

Combination therapy with androgen receptor N‐terminal domain antagonist EPI‐7170 and enzalutamide yields synergistic activity in AR‐V7‐positive prostate cancer

et al. 2020

View full text Add to dashboard Cite

Resistance of castration-resistant prostate cancer (CRPC) to enzalutamide and abiraterone involves the expression of constitutively active, truncated androgen receptor (AR) splice variants (AR-Vs) that lack a C-terminal ligand-binding domain (LBD). Both full-length AR and truncated AR-Vs require a functional N-terminal domain (NTD) for transcriptional activity thereby providing rationale for the development of ralaniten (EPI-002) as a first-in-class antagonist of the AR-NTD. Here, we evaluated the antitumor effect of a next-generation analog of ralaniten (EPI-7170) as a monotherapy or in combination with enzalutamide in prostate cancer cells that express AR-V7 that were resistant to enzalutamide. EPI-7170 had 8-9 times improved potency compared to ralaniten. Enzalutamide increased levels of AR-V7 and expression of its target genes. Knockdown of AR-V7 restored sensitivity to enzalutamide, indicating a role for AR-V7 in the mechanism of resistance. EPI-7170 inhibited expression of genes transcriptionally regulated by full-length AR and AR-V7. A combination of EPI-7170 and enzalutamide resulted in synergistic inhibition of proliferation of enzalutamide-resistant cells that was consistent with results from cell cycle and clonogenic assays. In addition, this drug enhanced the antitumor effect of enzalutamide in enzalutamide-resistant CRPC preclinical models. Thus, a combination therapy targeting both the NTD and LBD of AR, and thereby blocking both full-length AR and AR-Vs, has potential for the treatment of enzalutamide-resistant CRPC.

show abstract

Androgen receptor amplification is reflected in the transcriptional responses of Vertebral-Cancer of the Prostate cells

Cited by 45 publications

References 44 publications

Identification of response pathways of prostate cancer cell lines in Hans Clevers Media

Identification of response pathways of prostate cancer cell lines in Hans Clevers Media

Modulation of the Androgen Receptor Axis

Combination therapy with androgen receptor N‐terminal domain antagonist EPI‐7170 and enzalutamide yields synergistic activity in AR‐V7‐positive prostate cancer

Contact Info

Product

Resources

About