Loss of scinderin decreased expression of epidermal growth factor receptor and promoted apoptosis of castration‐resistant prostate cancer cells

Abstract

Most patients with prostate cancer will eventually develop the castration‐resistant form characterised by metastasis. Cytoskeleton constituents, including F‐actin, play important roles in maintaining epithelial integrity and their disruption is a major cause of cancer progression. We previously showed that scinderin (SCIN), an important regulator of F‐actin organisation, is highly expressed in poorly differentiated cancer tissues. This study aimed to explore the mechanism of its regulation of cell proliferation. We discovered that SCIN knockdown significantly downregulated epidermal growth factor receptor (EGFR) protein expression, and inhibited epidermal growth factor (EGF)‐mediated cell proliferation and activation of the downstream mitogen‐activated protein kinase kinase (MEK)/extracellular signal‐regulated kinase (ERK) signalling pathway. Silencing of SCIN promoted apoptosis in two cell lines (PC‐3 and DU145), inhibited B‐cell lymphoma‐extra‐large (Bcl‐xl) expression and activated caspase signalling. Furthermore, in vivo studies showed that SCIN deletion slowed tumour growth and decreased EGFR expression. Thus, we conclude that SCIN promotes prostate cancer cell survival by stabilising EGFR and MEK/ERK signalling.

Aberrant Scinderin Expression Correlates With Liver Metastasis and Poor Prognosis in Colorectal Cancer

“…Although the correlation between SCIN and cancer has been revealed, gradually, the role of SCIN in tumor development and progression was controversial among different researches. SCIN expression in megakaryoblastic leukemia cells promoted cell apoptosis and impaired cell proliferation and tumor formation (Zunino et al, 2001), which is contrary to our study and others (Lai et al, 2018; Qiao et al, 2018). Another study found high levels of SCIN expression in gastric cancer tissue correlated with poor prognosis.…”

“…In prostate cancer, SCIN knockdown significantly downregulated the protein expression of epidermal growth factor receptor (EGFR), impaired cell proliferation-mediated by epidermal growth factor, and inhibited the signaling pathway activation of the downstream mitogen-activated protein kinase (MEK) and extracellular signal-regulated kinase (ERK). SCIN knockdown promoted prostate cell apoptosis by inhibition of B-cell lymphoma-extra-large (Bcl-xl) expression and caspase signaling (Lai et al, 2018). However, the clinical significance and molecular mechanism for SCIN in CRC remain unknown.…”

Interplay of Epidermal Growth Factor Receptor and Signal Transducer and Activator of Transcription 3 in Prostate Cancer: Beyond Androgen Receptor Transactivation

“…The EGFR maintains cell survival by the following main cascades: The SRC proto-oncogene, non-receptor tyrosine kinase (Src)/mitogen-activated protein kinase (MAPK) cascade, and phosphatidylinositol 3-kinase (PI3K)/AKT signaling. Src phosphorylates MAPK kinase (MEK) with/without the paxillin (PXN) intermediate, followed by MAPK1 (also named extracellular signal-regulated kinase (ERK)) activation to upregulate pro-survival factors, such as BCL2-like 1 (Bcl-xL), matrix metalloproteases (MMPs), and Elk1/c-Fos [ 36 , 37 , 38 , 39 , 40 ]. Meanwhile, MEK phosphorylates Y-box-binding protein 1 (YB-1), which collaborates with ribosomal S6 kinase (RSK) and Raf-1 for the survival of gene expressions [ 41 , 42 ] ( Figure 2 ).…”

“…Src could activate both AR signaling and MEK/ERK or MEK/Y-box binding protein 1 (YB-1) signaling, which activate growth-related transcription factors. This figure is a summary of reference [ 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. A black solid arrow represents signal transduction; a red arrow represents cell fate.…”

“…Collectively, EGFR signaling maintains cell survival under ADT and maintains expressions of pro-survival factors. In the upstream of EGFR signaling, several transducers were identified, including the scinderin (SCIN)/ubiquitin-specific peptidase 39 (USP39)/protein-tyrosine-phosphatase of regenerating liver 1 (PRL1) as activators and microRNA (miR)-146a/miR-27a-5p/CKLFlike MARVEL transmembrane domain containing 5 (CMTM5) as inhibitors [37,[48][49][50][51] (Figure 4). During ADT, the EGFR upregulates its coactivators, ErbB2 and ErbB3, which promote androgen-sensitive cell survival under castration conditions [52].…”