Prostatic osteopontin expression is associated with symptomatic benign prostatic hyperplasia

Popovics, Petra; Awadallah, Wisam N.; Kohrt, Sarah E.; Case, Thomas C.; Miller, Nicole L.; Ricke, Emily A.; Huang, Wei; Ramirez‐Solano, Marisol; Liu, Qi; Vezina, Chad M.; Matusik, Robert J.; Ricke, William A.; Grabowska, Magdalena M.

doi:10.1101/2019.12.23.887612

Cited by 3 publications

(2 citation statements)

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“…Although chronic inflammation is associated with the severity and progression of BPH/LUTS, 33 its pathogenetic role, if any, is unresolved. Since prostate volume is associated with chronic inflammation, 33 a potential growth‐promoting effect of pro‐inflammatory factors such as cytokines and prostaglandins has been suggested 31,34,35 . Areas of inflammation are also associated with increased COX2 within luminal epithelial cells, 31 consistent with our data.…”

Section: Discussionsupporting

confidence: 88%

The prostaglandin pathway is activated in patients who fail medical therapy for benign prostatic hyperplasia with lower urinary tract symptoms

et al. 2021

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Background Little is known about how benign prostatic hyperplasia (BPH) develops and why patients respond differently to medical therapy designed to reduce lower urinary tract symptoms (LUTS). The Medical Therapy of Prostatic Symptoms (MTOPS) trial randomized men with symptoms of BPH and followed response to medical therapy for up to 6 years. Treatment with a 5α‐reductase inhibitor (5ARI) or an alpha‐adrenergic receptor antagonist (α‐blocker) reduced the risk of clinical progression, while men treated with combination therapy showed a 66% decrease in risk of progressive disease. However, medical therapies for BPH/LUTS are not effective in many patients. The reasons for nonresponse or loss of therapeutic response in the remaining patients over time are unknown. A better understanding of why patients fail to respond to medical therapy may have a major impact on developing new approaches for the medical treatment of BPH/LUTS. Prostaglandins (PG) act on G‐protein‐coupled receptors (GPCRs), where PGE2 and PGF2 elicit smooth muscle contraction. Therefore, we measured PG levels in the prostate tissue of BPH/LUTS patients to assess the possibility that this signaling pathway might explain the failure of medical therapy in BPH/LUTS patients. Method Surgical BPH (S‐BPH) was defined as benign prostatic tissue collected from the transition zone (TZ) of patients who failed medical therapy and underwent surgical intervention to relieve LUTS. Control tissue was termed Incidental BPH (I‐BPH). I‐BPH was TZ obtained from men undergoing radical prostatectomy for low‐volume, low‐grade prostatic adenocarcinoma (PCa, Gleason score ≤ 7) confined to the peripheral zone. All TZ tissue was confirmed to be cancer‐free. S‐BPH patients divided into four subgroups: patients on α‐blockers alone, 5ARI alone, combination therapy (α‐blockers plus 5ARI), or no medical therapy (none) before surgical resection. I‐BPH tissue was subgrouped by prior therapy (either on α‐blockers or without prior medical therapy before prostatectomy). We measured prostatic tissue levels of prostaglandins (PGF2α, PGI2, PGE2, PGD2, and TxA2), quantitative polymerase chain reaction levels of mRNAs encoding enzymes within the PG synthesis pathway, cellular distribution of COX1 (PTGS1) and COX2 (PTGS2), and tested the ability of PGs to contract bladder smooth muscle in an in vitro assay. Results All PGs were significantly elevated in TZ tissues from S‐BPH patients (n = 36) compared to I‐BPH patients (n = 15), regardless of the treatment subgroups. In S‐BPH versus I‐BPH, mRNA for PG synthetic enzymes COX1 and COX2 were significantly elevated. In addition, mRNA for enzymes that convert the precursor PGH2 to metabolite PGs were variable: PTGIS (which generates PGI2) and PTGDS (PGD2) were significantly elevated; nonsignificant increases were observed for PTGES (PGE2), AKR1C3 (PGF2α), and TBxAS1 (TxA2). Within the I‐BPH group, men responding to α‐blockers for symptoms of BPH but requiring prostatectomy for PCa did not show elevated levels of COX1, COX2, or PGs. By immun...

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Section: Discussionsupporting

confidence: 88%

The prostaglandin pathway is activated in patients who fail medical therapy for benign prostatic hyperplasia with lower urinary tract symptoms

et al. 2021

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“…BPH is a wide-spread chronic condition in elderly males and may significantly affect the quality of life [5,21]. Multiple factors are associated with the pathogenesis of BPH, including chronic inflammation, age-related changes, and disturbance in hormone balance [22,23]. A large body of evidence suggests that the majority of patients can achieve satisfactory relief of symptoms with pharmacological therapy [24].…”

Section: Discussionmentioning

confidence: 99%

Influence of Androgen Receptor Antagonist MDV3100 Therapy on Rats With Benign Prostatic Hyperplasia

Yang¹,

Xu²,

Zhuang³

2021

Int Neurourol J

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Purpose: To probe the effect and mechanism of androgen receptor antagonist MDV3100 on benign prostatic hyperplasia (BPH) of ratsMethods: BPH rat model was induced by testosterone propionate. Then antagomir-miR-21-3p or agomir-miR-21-3p was injected into rats before MDV3100 treatment. The prostate index was measured by weighing the wet weight of the rat prostate. The structural morphology of rat prostate was observed after hematoxylin & eosin staining. Immunohistochemistry was applied to evaluate the expression levels of Ki-6 and inflammatory cytokines (interleukin [IL]-6, IL-18, and tumor necrosis factor-α) in rat prostate tissues. Quantitative reverse transcription polymerase chain reaction was utilized for assessment of miR-21-3p expression, and Western blot for the performance of the phosphorylation levels of IKKα and p65.Results: Injection of testosterone propionate caused increased prostate gland hyperplasia, heightened miR-21-3p level, and activated nuclear factor-kappa B (NF-κB) signaling pathway. Additionally, BPH was accompanied by inflammatory response, as evidenced by enhanced expressions of Ki-67 and inflammatory cytokines. MDV3100 exposure ameliorated BPH and suppressed miR-21-3p expression. Overexpression of miR-21-3p intensified BPH and inflammation level, while knockdown of miR-21-3p relieved BPH. The coeffect of miR-21-3p upregulation and MDV3100 subjection led to higher inflammatory response, elevated phosphorylation levels of IKKα and p65 than MDV3100 treatment alone.Conclusions: Androgen receptor antagonist MDV3100 alleviates BPH and inflammatory response through miR-21-3p downregulation and NF-κB signaling pathway blockade.

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SLX4IP-mediated telomere maintenance is essential for androgen receptor-independent castration-resistant prostate cancer

Mangosh

Awadallah

Grabowska

et al. 2020

Preprint

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In advanced prostate cancer, resistance to androgen deprivation therapy is achieved through numerous mechanisms, including loss of the androgen receptor (AR) allowing for AR-independent growth.Therapeutic options are limited for AR-independent castration-resistant prostate cancer, and defining mechanisms critical for its survival is of utmost importance for targeting this lethal disease. Our studies have focused on defining the telomere maintenance mechanism (TMM) required for castration-resistant prostate cancer (CRPC) cell survival. TMMs are responsible for telomere elongation to instill replicative immortality and prevent senescence, with the two TMM pathways available being telomerase and alternative lengthening of telomeres (ALT). Here, we show that AR-independent CRPC exhibits ALT hallmarks and limited telomerase expression and activity, whereas AR-dependent models use telomerase for telomere maintenance. AR-independent CRPC exhibited elevated levels of SLX4IP, a protein implicated in TMM switching. SLX4IP overexpression in AR-dependent CRPC C4-2B cells promoted ALT hallmarks in vitro. SLX4IP knockdown in AR-independent CRPC cells (DU145 and PC-3) led to the loss of ALT hallmarks, dramatic telomere shortening, induction of senescence, and reduced tumor volume. Using an in vitro model of CRPC progression, induction of neuroendocrine differentiation in AR-dependent CRPC cells promoted ALT hallmarks in an SLX4IP-dependent manner. Lack of sufficient SLX4IP expression prevented ALT hallmarks rendering a TMM deficient environment, thus inducing senescence. This study demonstrates a unique reliance of AR-independent CRPC on SLX4IP-mediated ALT. Furthermore, ALT hallmark inhibition via SLX4IP induces senescence, thereby abolishing the replicative immortality of AR-independent CRPC.

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Prostatic osteopontin expression is associated with symptomatic benign prostatic hyperplasia

Cited by 3 publications

References 58 publications

The prostaglandin pathway is activated in patients who fail medical therapy for benign prostatic hyperplasia with lower urinary tract symptoms

The prostaglandin pathway is activated in patients who fail medical therapy for benign prostatic hyperplasia with lower urinary tract symptoms

Influence of Androgen Receptor Antagonist MDV3100 Therapy on Rats With Benign Prostatic Hyperplasia

SLX4IP-mediated telomere maintenance is essential for androgen receptor-independent castration-resistant prostate cancer

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