Perspectives for Targeting Ezrin in Cancer Development and Progression

Abstract

Recent advances have been made in understanding molecular markers involved in cancer malignancy, resulting in better tumor staging and identifying new potential therapeutic targets. Ezrin (EZR), a member of the ezrin, radixin, moesin (ERM) protein family, is essential for linking the actin cytoskeleton to the cell membrane and participates in the signal transduction of key signaling pathways such as Rho GTPases and PI3K/AKT/mTOR. Clinical and preclinical studies in a wide variety of solid and hematological tumors indicate that (i) EZR is highly expressed and predicts an unfavorable clinical outcome, and (ii) EZR inhibition reduces proliferation, migration, and invasion in experimental models. The development of pharmacological inhibitors for EZR (or the signaling mediated by it) has opened a new round of investigation, but studies are still limited. The scope of the present review is to survey studies on the expression and clinical impact of EZR in cancer, as well as studies that perform interventions on the function of this gene/protein in cancer cells, providing proof-of-concept of its antineoplastic potential.

Two-Dimensional and Spheroid-Based Three-Dimensional Cell Culture Systems: Implications for Drug Discovery in Cancer

“…Migration assays, such as wound-healing and Boyden chamber assays, revealed that treating MDA-MB-231 cells with a low dose of epirubicin resulted in inhibited migration. Additionally, a decrease in the expression of ezrin, a protein from the ERM family that participates in the linking of the actin cytoskeleton to the cell membrane, was observed [109,110]. These studies contribute to a deeper understanding of chemotherapy drugs' impact on cellular processes beyond their primary mechanisms of action, offering insight into future drug development and combined strategies of treatments.…”

Ezrin Inhibition Overcomes Acquired Resistance to Vemurafenib in BRAFV600E-Mutated Colon Cancer and Melanoma Cells In Vitro

“…To test this hypothesis, we treated the resistant cells with five different concentrations of vemurafenib (starting from IC50 concentration down to four different sub-toxic concentrations) in combination with three concentrations of pharmacological ezrin inhibitor NSC305787 at IC50 and two sub-toxic concentrations and measured the anti-proliferative effect of treatment combinations by MTT assay. Selective ezrin inhibitor NSC305787 is an experimental anti-cancer agent that has been so far evaluated only in pre-clinical studies which showed that NSC305787 has acceptable toxicity and pharmacokinetics profiles in murine models [ 12 ]. Our results revealed that pharmacological inhibition of ezrin markedly increased the cell-growth-inhibitory activity of vemurafenib in the resistant RKO cells in a concentration-dependent manner when compared to a single-agent treatment with vemurafenib ( Figure 3 A).…”

“…The PPI network analysis in STRING ( Figure 1 D) indicated the interconnection of ezrin with CD44, which is congruent with literature data reporting that ezrin binds to cell-adhesion molecule CD44 implicated in cancer-cell migration and metastasis [ 14 ]. Another interesting protein candidate emerging from the ezrin network appeared to be AKT, the component of the PI3K/AKT signaling pathway activated by ezrin in different cancer types [ 12 ] and previously demonstrated to mediate de novo vemurafenib resistance in BRAFV600E-expressing RKO cells [ 18 ]. Finally, c-Myc expression was evaluated for combined anti-proliferative effects based on the previous findings showing that ezrin positively regulates c-Myc protein levels in prostate cancer cells by activating the AKT signaling pathway downstream from ezrin that controls c-Myc expression at the gene and protein level [ 19 ].…”

“…Bioinformatics analysis of obtained proteomics data indicated actin-cytoskeleton linker protein ezrin as a highly ranked protein significantly associated with vemurafenib resistance whose overexpression in the resistant cells was additionally confirmed at the gene and protein level. Ezrin belongs to the ezrin, radixin, moesin (ERM) protein family and has a demonstrated role as a driver of tumour progression and metastatic spread whose high expression correlates with unfavourable clinical outcome in different cancer types [ 12 , 13 ]. Ezrin regulates cancer-cell survival and metastatic cascade by controlling cytoskeletal remodelling and cellular signalling pathways [ 13 ].…”