Nimotuzumab inhibits epithelial–mesenchymal transition in prostate cancer by targeting the Akt/YB‐1/AR axis

Abstract

Nimotuzumab is a humanized anti‐EGF monoclonal antibody that has been approved for treating different cancers. However, few studies have examined its therapeutic potential in prostate cancer (PC), a most common and highly aggressive malignancy among male population. We used both LNCaP, and PC3 and PC3‐AR (androgen receptor) cells as the model system and assessed the effects of nimotuzumab on epithelial–mesenchymal transition (EMT) in vitro and in vivo. The EMT makers were detected by immunohistochemistry, qRT‐PCR and Western blot. MTT, wound healing assay, and transwell assay were used to measure cell viability, migration, and invasion, respectively. For mechanistic understanding, we evaluated the significance of Akt/Y‐box binding protein‐1 (YB‐1)/AR axis in nimotuzumab‐induced EMT by overexpressing AR, activating Akt using SC79, and/or downregulating YB‐1 using siRNA. Nimotuzumab suppressed the xenograft growth from both LNCaP and PC3 cells in vivo, which was associated with reduced EMT. Consistently, nimotuzumab inhibited proliferation, cell‐cycle progression, EMT, and migration/invasion, but stimulated apoptosis of both LNCaP and PC3‐AR cells in vitro. On the molecular level, nimotuzumab inactivated Akt and YB‐1 and reduced the expression of AR. Boosting AR expression in LNCaP and PC3‐AR cells antagonized the action of nimotuzumab, at least partially restored EMT, and enhanced the migration/invasion. We also found that Akt was essential for controlling YB‐1 activation, and both critical for regulating the levels of AR and EMT‐related biomarkers. In this study, we presented our novel findings that by targeting the Akt/YB‐1/AR axis, nimotuzumab significantly inhibited EMT of PC cells. Considering that EMT is a critical mechanism contributing to the metastatic spread of cancer cells, nimotuzumab may become a promising therapy for alleviating the malignant progression of PC. © 2019 IUBMB Life, 1–14, 2019

Telmisartan anti‐cancer activities mechanism through targeting N‐cadherin by mimicking ADH‐1 function

“…Small molecules, which is composed about 75% of the anticancer FDAapproved drugs, have an extended history of using as drugs for the treatment of many diseases including diabetes, hypertension, infections, heart failure, rhinitis and cancers. 8,9 Previous study reported a novel peptide, ADH-1, that inhibit Ncadherin (a marker of EMT) function. 10 Yarom et al 11 showed that ADH-1 was commonly well tolerated up to a dose of 1000 mg/m 2 when administered every three weeks in patients with incurable solid tumours.…”

The roles of Y-box-binding protein (YB)-1 and C-X-C motif chemokine ligand 14 (CXCL14) in the progression of prostate cancer via extracellular-signal-regulated kinase (ERK) signaling

“…AKT regulates many cellular functions, including growth, proliferation, and survival. A previous study suggested that both EGFR and AKT are upstream signaling activators of YB-1 [ 18 ] and are essential for controlling YB-1 activation in breast cancer [ 31 , 32 ]. In melanoma cells, the MAPK and PI3K/AKT signaling pathways activate and increase YB-1 phosphorylation [ 11 ].…”

Gene amplification of YB‐1 in castration‐resistant prostate cancer in association with aberrant androgen receptor expression

“…These data suggest that other mechanisms, including epigenetic regulation, are also involved in YB‐1 overexpression. Actually, several signal transduction pathways, such as Akt, ERK, and ribosomal S6 kinase (RSK), as well as transcription factors, such as Twist1, were shown to regulate YB‐1 expression in prostate cancer 9,11‐14 . Collectively, both genetic and epigenetic mechanisms are considered to contribute to YB‐1 overexpression in CRPC.…”

“…[7][8][9][10][11] As a molecular mechanism, YB-1 was indicated to regulate AR and AR variant expressions, leading to progression to CRPC. 7,11,12 Furthermore, YB-1 expression was correlated with AR expression in ADT-naïve prostate cancer. 7 Consistently, YB-1 expression was increased in highly malignant tumors and associated with poor prognosis.…”

“…In prostate cancer, YB‐1 expression was reported to be increased in ADT and CRPC, and associated with resistance to ADT and AR‐pathway inhibitors (ARPIs) like abiraterone and enzalutamide in preclinical models 7‐11 . As a molecular mechanism, YB‐1 was indicated to regulate AR and AR variant expressions, leading to progression to CRPC 7,11,12 . Furthermore, YB‐1 expression was correlated with AR expression in ADT‐naïve prostate cancer 7 .…”