Role of protein phosphatases in genitourinary cancers

Igawa, Tsukasa

doi:10.1111/iju.13197

Cited by 4 publications

(2 citation statements)

References 92 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One possibility is the oncogenic activation of protein tyrosine kinases because of defective control molecules, such as protein phosphatases that are not able to properly control their substrate kinase activity. Protein phosphatases have been a key focus of PCa research as crucial regulators of AR and multiple kinase signaling pathways via phosphorylation and dephosphorylation‐dependent processes (45). Most importantly, phosphatase and tensin homolog (PTEN), a tumor suppressor and DUSP, has been extensively studied in human PCas (46, 47).…”

Section: Discussionmentioning

confidence: 99%

DUSP22 suppresses prostate cancer proliferation by targeting the EGFR‐AR axis

Lin

Chang

et al. 2019

The FASEB Journal

View full text Add to dashboard Cite

Dual-specificity phosphatases (DUSPs) regulate the activity of various downstream kinases through serine or threonine or tyrosine dephosphorylation. Loss of function and aberrant expression of DUSPs has been implicated in cancer progression and poor survival, yet the function of DUSP22 in prostate cancer (PCa) cells is not clear. Gene Expression Omnibus and cBioPortal microarray database analyses showed that DUSP22 expression was lower in PCa tissues than normal prostate tissues, and altered DUSP22 expression was associated with shorter progression-free and disease-free survival of patients with PCa. Exogenous DUSP22 expression in LNCaP, PC3, and C4-2B PCa cells inhibited cellular proliferation and colony formation, supporting a growth inhibitory role for DUSP22 in PCa cells. DUSP22 expression significantly attenuated epidermal growth factor (EGF) receptor (EGFR) and its downstream ERK1/2 signaling by dephosphorylation. However, DUSP22 failed to suppress the growth of CWR22Rv1 and DU145 cells with elevated phosphorylated (p-)ERK1/2 levels. A serine-to-alanine mutation at position 58, a potential ERK1/2-targeted phosphorylation site in DUSP22, was sufficient to suppress growth of CWR22Rv1 cells with elevated p-ERK1/2 levels, suggesting a mutually antagonistic relationship between DUSP22 and ERK1/2 dependent on phosphorylation status. We showed that DUSP22 can suppress prostate-specific antigen gene expression through phosphatase-dependent pathways, suggesting that DUSP22 is an important regulator of the androgen receptor (AR) in PCa cells. Mechanistically, DUSP22 can interact with AR as a regulatory partner and interfere with EGF-induced AR phosphorylation at Tyr534, suggesting that DUSP22 serves as a crucial suppressor of both EGFR and AR-dependent signaling in PCa cells via dephosphorylation. Our findings indicate that loss of function of DUSP22 in PCa cells leads to aberrant activation of both EGFR-ERKs and AR signaling and ultimately progression of PCa, supporting the potential for novel therapeutic design of harnessing DUSP22 in the treatment of

show abstract

Section: Discussionmentioning

confidence: 99%

DUSP22 suppresses prostate cancer proliferation by targeting the EGFR‐AR axis

Lin

Chang

et al. 2019

The FASEB Journal

View full text Add to dashboard Cite

show abstract

“…One substance that plays a role in the negative regulation of tyrosine phosphorylation is protein tyrosine phosphatase (PTP). Although Igawa et al have reported that prostatic acid phosphatase is involved in the negative control of prostate cancer cell proliferation through regulation of PTKs, there are far fewer reports on PTPs in prostate cancer than there are on PTKs (31,32), hence, the details of the mechanism of action remain largely unknown.…”

Section: Discussionmentioning

confidence: 99%

Low-molecular-weight Protein Tyrosine Phosphatase Is a Possible Biomarker for Predicting Postoperative Biochemical Recurrence in Prostate Cancer With Negative Surgical Margins

et al. 2019

Self Cite

View full text Add to dashboard Cite

Background/Aim: For prostate cancer, positive surgical margins are considered an important predictor of biochemical recurrence. However, biochemical recurrence is observed in approximately 20% of cases, even with negative surgical margins, and some cases require salvage therapy. The elevated expression of low-molecular-weight protein tyrosine phosphatase (LMW-PTP, MW 18 kDa) is associated with a poor prognosis of certain cancers. In this study, we investigated whether the LMW-PTP expression levels could be used as a biomarker of recurrence in prostate cancer with negative surgical margins. Materials and Methods: The subjects of this retrospective study were 119 patients who underwent total prostatectomy with negative resection margins. LMW-PTP expression was categorized either as a highexpression group or as a low-expression group bye two pathologists. Subsequently, we examined the relationship between LMW-PTP expression levels and clinicopathological factors including biochemical recurrence. Results: Evaluation of the immunostained samples by two pathologists was highly reliable, with an Intraclass correlation (ICC) score for two distinct measurements of 0.77 and 0.98, respectively. Seventythree patients (61.3%) were placed in the LMW-PTP high expression group; and 46 patients (38.7%) were placed in the low expression group. The log-rank test revealed early biochemical recurrence in the high LMW-PTP expression group (p=0.0001). In addition, pathological T stage (p=0.004), lymphatic invasion (p=0.0456), Ki-67 labeling index (p=0.0002), and biochemical recurrence (p<0.0001) were more frequently identified in the LMW-PTP high expression group. Furthermore, multivariate analyses revealed that a high LMW-PTP expression level was an independent prognostic factor for biochemical recurrence (HR=3.14, 95% CI=1.37-8.07, p=0.0057). In addition, Ki-67 labeling indices were significantly higher in the high-expression group compared to the low-expression group (p<0.0001). Conclusion: LMW-PTP can be assessed using a single immunostaining protocol in a highly reproducible fashion. Tt may, thus, be applied clinically to establish the required postoperative follow-up period and determine the necessity for salvage therapy in cases of prostate cancer with negative surgical margins. LMW-PTP has the potential to be a highly useful prognostic biomarker and a therapeutic target in conjunction with other factors, such as the Gleason Score, the pathological T stage and the PSA level.Prostate cancer is the most common type of cancer in men in developed countries. In the United States, one in five new cases of diagnosed cancer is in the prostate, while in Japan, the increasingly widespread use of prostate-specific antigen (PSA) testing has led to prostate cancer becoming the most prevalent type of cancer in men in 2016 (1). Treatment options for localized prostate cancer include radical prostatectomy (2), radiotherapy (external & internal radiation) (3), and active surveillance (4). However, changes in surgical procedures (from open surger...

show abstract