Effect of Extracellular Signal-Regulated Protein Kinase 5 Inhibition in Clear Cell Renal Cell Carcinoma

Background: Extracellular signal-regulating kinase 5 (ERK5) has been implicated in many cellular functions, including survival, proliferation, and vascularization. Our objectives were to examine the expression and effect of ERK5 in clear.

Methods: The expressions of ERK5 and its regulating micro-RNA miR-143 were investigated using immunohistochemistry and quantitative reverse transcriptase PCR in surgical specimens of ccRCC patients. With invitro and in vivo studies, we used pharmacologic ERK5 inhibitor XMD8-92, RNA interference, pre-miR-143 transduction, Western blotting, MTS assay, apoptosis assay, and subcutaneous xenograft model.

Results: A strong ERK5 expression in surgical specimen was associated with high-grade (p = 0.01), high-recurrence free rate (p = 0.02), and high cancer-specific survival (p = 0.03). Expression levels of ERK5 and miR-143 expression level were correlated (p = 0.049). Pre-miR-143 transduction into ccRCC cell A498 suppressed ERK5 expression. ERK5 inhibition enhanced cyclin-dependent kinase inhibitor p21 expression and decreased anti-apoptotic molecules BCL2, resulting in decreased cell proliferation and survival both in ccRCC and endothelial cells. In the xenograft model, ERK5 inhibitor XMD8-92 suppressed tumor growth.

Conclusions: ERK5 is regulated by miR-143, and ERK5 inhibition is a promising target for ccRCC treatment.

 

Comments:

The study focuses on investigating the expression and role of extracellular signal-regulating kinase 5 (ERK5) in clear cell renal cell carcinoma (ccRCC). Here is a breakdown of the main findings and conclusions:

Background: ERK5 is involved in various cellular functions, including survival, proliferation, and vascularization.

The objective of the study was to examine the expression and impact of ERK5 in ccRCC.
 

Methods: Surgical specimens from ccRCC patients were analyzed using immunohistochemistry and quantitative reverse transcriptase PCR to assess the expression of ERK5 and its regulating micro-RNA, miR-143.

In vitro and in vivo experiments were conducted using the pharmacologic ERK5 inhibitor XMD8-92, RNA interference, pre-miR-143 transduction, Western blotting, MTS assay, apoptosis assay, and a subcutaneous xenograft model.
 

Results: Strong ERK5 expression in surgical specimens was associated with high-grade ccRCC, high recurrence-free rate, and high cancer-specific survival.

There was a correlation between the expression levels of ERK5 and miR-143.
Transduction of pre-miR-143 into ccRCC cells suppressed ERK5 expression.
Inhibition of ERK5 led to increased expression of the cyclin-dependent kinase inhibitor p21 and decreased expression of the anti-apoptotic molecule BCL2, resulting in decreased cell proliferation and survival in both ccRCC and endothelial cells.
The ERK5 inhibitor XMD8-92 suppressed tumor growth in a xenograft model.
 

Conclusions: The study concludes that ERK5 is regulated by miR-143.

Inhibition of ERK5 shows promise as a target for ccRCC treatment.
 

In summary, the study provides evidence for the involvement of ERK5 in ccRCC and suggests that targeting ERK5 could be a potential therapeutic strategy for the treatment of this type of kidney cancer.

Related Products

Cat.No.	Product Name	Information
S7525	XMD8-92	XMD8-92 is a potent and selective dual inhibitor of big map kinase (BMK1, ERK5) and bromodomain-containing proteins (BRDs, BET) with Kd of 80 nM and 170 nM for ERK5 and BRD4(1), respectively.

Related Targets

ERK Epigenetic Reader Domain