SPP1 Promotes Enzalutamide Resistance and Epithelial‐Mesenchymal‐Transition Activation in Castration‐Resistant Prostate Cancer via PI3K/AKT and ERK1/2 Pathways

Abstract

The bottleneck arising from castration-resistant prostate cancer (CRPC) treatment is its high metastasis potential and antiandrogen drug resistance, which severely affects survival time of prostate cancer (PCa) patients. Secreted phosphoprotein 1 (SPP1) is a cardinal mediator of tumor-associated inflammation and facilitates metastasis. In our previous study, we firstly revealed SPP1 was a potential hub signature for predicting metastatic CRPC (mCRPC) development. Herein, we integrated multiple databases to explore the association of SPP1 expression with prognosis, survival, and metastatic levels in CRPC progression and investigated SPP1 expression in PCa tissues and cell lines. Next, PCa cell lines with overexpression or depletion of SPP1 were established to study the effect of SPP1 on enzalutamide sensitivity and adhesion and migration of prostate cancer cell lines and further explore the underlying regulatory mechanisms. Bioinformatics analysis, polymerase chain reaction (PCR), immunohistochemical staining, and western blot results suggested SPP1 upregulation had strong relationship with the malignant progression of CRPC and enzalutamide resistance. SPP1 knockdown enhanced enzalutamide sensitivity and repressed invasion and migration of prostate cancer cells. Importantly, upregulating SPP1 promoted, while silencing SPP1 attenuated epithelial-mesenchymal-transition (EMT). Our results further demonstrated that SPP1 overexpression maintains the activation of PI3K/AKT and ERK1/2 signaling pathways. Overall, our findings unraveled the functional role and clinical significance of SPP1 in PCa progression and help to discover new potential targets against mCRPC.

Exploring potential targets of Actinidia Chinensis Planch root against hepatocellular carcinoma based on network pharmacology and molecular docking and development and verification of immune-associated prognosis features for hepatocellular carcinoma

“…SPP1, also termed osteopontin (OPN), is an important extracellular glycoprotein in the small integrin-binding ligand N-linked glycoprotein (SIBLING) family (47). Much research has shown that SPP1 is closely linked with processes such as growth, adhesion, invasion, angiogenesis, and metastasis in many malignant tumors (48)(49)(50). In liver cancer cells, SPP1 can not only bind to CD44 and activate the PI3K/Akt signaling pathway, but it can also activate integrins and induce the expression of NF-κB to inhibit apoptosis.…”

Osteopontin and its downstream carcinogenic molecules: regulatory mechanisms and prognostic value in cancer progression

“…Therefore, the combination of OPN, HIFtargeted therapies may have clinical significance, while targeted inhibition of OPN, VEGF and HIF-OPN regulates the expression of EMT-related proteins. EMT is the process by which epithelial cells lose intercellular junctions and apical-basal polarity and transition to mesenchymal cells, and this transition induces epithelial cells to acquire fibroblastic properties that promote cell motility and the formation of new membrane protrusions, and this is a key event in the acquisition of migratory and invasive capacity by cancer cells of epithelial origin [24]. E-cadherin, an important adhesion molecule that maintains epithelial cell junctions and is a specific protein representing the epithelial cell phenotype, is expressed at reduced levels in EMT; similarly, N-cadherin, Vimentin -catenin, which are specific proteins for the mesenchymal cell phenotype, are expressed at elevated levels in EMT [24,42].…”

“…EMT is the process by which epithelial cells lose intercellular junctions and apical-basal polarity and transition to mesenchymal cells, and this transition induces epithelial cells to acquire fibroblastic properties that promote cell motility and the formation of new membrane protrusions, and this is a key event in the acquisition of migratory and invasive capacity by cancer cells of epithelial origin [24]. E-cadherin, an important adhesion molecule that maintains epithelial cell junctions and is a specific protein representing the epithelial cell phenotype, is expressed at reduced levels in EMT; similarly, N-cadherin, Vimentin -catenin, which are specific proteins for the mesenchymal cell phenotype, are expressed at elevated levels in EMT [24,42]. The EMT transcription factors (EMT-TFs) such as Snail, Twist and Slug are key inducers of EMT development, and they are involved in EMT development by suppressing E-cadherin expression and promoting N-cadherin, V -catenin expression, which in turn promote cancer metastasis and invasion [43,44].…”

“…The CD44 receptor binding domain is located at the carboxyl end of OPN and binds mainly to various splicing variants of the CD44 receptor (CD44v3, CD44v6 and CD44v7) [19]. With the assistance of integrin receptors or CD44 receptors, OPN regulates cell proliferation, adhesion and migration by activating -catenin and JAK/STAT [24][25][26]. Therefore, blocking the binding of OPN to integrin receptors and CD44 receptors may help treat OPN-mediated pathological diseases.…”

Drug resistance in metastatic castration-resistant prostate cancer: an update on the status quo

“…SPP1, an important extracellular matrix component secreted by multiple kinds of cell types including immune cells, fibroblasts, osteoclasts, smooth muscle, and epithelial cells, is overexpressed in many types of tumors [ 107 , 108 ] . In the GSE32269 dataset, SPP1 expression was shown to be significantly higher in the mCRPC group than in the primary PCa group.…”