Inhibition of EGFR signaling with Spautin-1 represents a novel therapeutics for prostate cancer.

Abstract

BACKGROUND:

Prostate cancer (PCa) remains a challenge worldwide. Due to the development of castration-resistance, traditional first-line androgen deprivation therapy (ADT) became powerlessness. Epidermal growth factor receptor (EGFR) is a well characterized therapeutic target to treat colorectal carcinoma and non-small cell lung cancer. Increasing studies have unraveled the significance of EGFR and its downstream signaling in the progression of castration-resistant PCa.

METHOD:

MTS, colony formation and Edu staining assays were used to analyze the cell proliferation of PCa cells. Flow cytometry was used to analyze PCa cell cycle distribution and cell apoptosis. Western blot was used to measure the expression of key proteins associated with cell cycle progression, apoptosis and EGFR signaling pathways. Transfection of exogenous small interfering RNA (siRNA) or plasmid was used to intervene specific gene expression. Nude mouse model was employed to test the in vivo effect of Spautin-1.

RESULTS:

The current study reveals that Spautin-1, a known inhibitor of ubiquitin-specific peptidase 10 (USP10) and USP13, inhibits EGFR phosphorylation and the activation of its downstream signaling. Inhibition of EGFR signaling induced by Spautin-1 leads to cell cycle arrest and apoptosis of PCa in a USP10/USP13 independent manner. The application of Spautin-1 reduces the expression of glucose transporter 1 (Glut1) and dramatically induces cell death under glucose deprivation condition. In vivo experiments show a potent anti-tumor effect of Spautin-1 alone and in combination with Enzalutamide.

CONCLUSION:

This study demonstrates the therapeutic potential of EGFR signaling inhibition by the use of Spautin-1 for PCa treatment.

• Authors: Yuning Liao, Zhiqiang Guo, Xiaohong Xia, Yuan Liu, Chuyi Huang, Lili Jiang, Xuejun Wang, Jinbao Liu, Hongbiao Huang
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 38 Issue 1 Pg. 157 (Apr 11 2019) ISSN: 1756-9966 [Electronic] England
• PMID: 30975171 (Publication Type: Journal Article)

Chemical References

• Benzamides
• Benzylamines
• Biomarkers, Tumor
• Glucose Transporter Type 1
• Nitriles
• Quinazolines
• spautin-1
• Cyclin D1
• Phenylthiohydantoin
• enzalutamide
• EGFR protein, human
• ErbB Receptors
• Extracellular Signal-Regulated MAP Kinases
• JNK Mitogen-Activated Protein Kinases
• Glucose

Topics

• Animals
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Benzamides
• Benzylamines (pharmacology)
• Biomarkers, Tumor
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin D1 (genetics)
• Disease Models, Animal
• ErbB Receptors (metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Glucose (metabolism)
• Glucose Transporter Type 1 (genetics, metabolism)
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Male
• Mice
• Models, Biological
• Molecular Targeted Therapy
• Nitriles
• Phenylthiohydantoin (analogs & derivatives, pharmacology)
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Quinazolines (pharmacology)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays