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

Abstract

(1) 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 cell renal cell carcinoma (ccRCC). (2) 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. (3) 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. (4) Conclusions: ERK5 is regulated by miR-143, and ERK5 inhibition is a promising target for ccRCC treatment.

Bone and Extracellular Signal-Related Kinase 5 (ERK5)

“…In the context of renal tumors, Kanno et al observed that upregulated ERK5 promotes proliferation and suppresses apoptosis in renal cancer cells. The inhibition of ERK5 led to elevated expression of the cyclin-dependent kinase inhibitor p21 and reduced levels of the anti-apoptotic molecule B-cell lymphoma 2 (BCL2) [79]. Arias et al confirmed that increased ERK5 levels foster proliferation, invasion, and metastasis in clear cell renal cell carcinoma, with a positive correlation between ERK5 expression and the disease's invasiveness and metastasis in fresh human samples [81].…”

Hemoglobin β Expression Is Associated with Poor Prognosis in Clear Cell Renal Cell Carcinoma

“…The tumors were fixed in 10% buffered formalin, embedded in paraffin, and the samples were coded. Paraffin sections were routinely stained with hematoxylin and eosin, and a pathological diagnosis was made as previously described [21]. Pathological evaluation was performed according to the 2016 World Health Organization classification [22] and the 2017 American Joint Committee on Cancer Tumor-Node Metastasis staging system.…”

Editorial for the Special Issue “MAPK in Health and Disease”

“…Another study delves into the prognostic implications of ERK5 in various cancers, including lung, prostate, and renal clear-cell carcinomas [ 4 ]. A higher ERK5 expression was correlated with a poorer prognosis in renal carcinoma patients.…”