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Background: Metastatic renal cell carcinoma (RCC) often develops resistance to first-line targeted therapy such as sunitinib. G-Protein-coupled estrogen receptor 1 (GPER1) agonist G-1 was recently reported to regulate RCC physiology but the role of G-1 in RCC tumorigenesis and sunitinib resistance remains largely unknown., Materials and Methods: Parental and sunitinib-resistant 786-O cells were treated with GPER1 agonist G-1, and quantitative phosphoproteomics was performed. Bioinformatic analyses and validations, including immunoblotting, cell migration, and cell cycle distribution, were performed., Results: G-1 repressed cell proliferation and migration in both parental and sunitinib-resistant 786-O cells. Phosphoproteomic signatures, including phosphoinositide 3-kinase and protein kinase B (PI3K-AKT) as well as other pathways, were up-regulated in sunitinib-resistant cells but application of G-1 reversed this effect. Among phosphoprotein candidates, activating transcription factor 2 (ATF2) Thr69/71 phosphorylation was antagonistically regulated by sunitinib resistance and G-1., Conclusion: Our results open up the possibility for managing RCC and sunitinib resistance by GPER1 agonist G-1 and its regulated pathways., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Tumor metastasis or recurrence often occurs in patients with curative resection of colorectal cancer (CRC). Placental-specific 8 (PLAC8), which has increased expression in stool, may be associated with CRC recurrence. Insights into the role of PLAC8 in CRC recurrence and its clinical significance may support to develop strategies for preventing CRC recurrence and deterioration. Clinical tissues, cell and animal models were used to clarify the roles of PLAC8 in CRC tumorigenesis, invasion, and migration. Next-generation sequencing of 16S ribosomal DNA has been used to assess the gut microbiota in stool of CRC patients. We found that PLAC8 was upregulated in tissues from patients with late-stage CRC. In our in vitro studies, PLAC8 was dynamically regulated in mitotic cells. Overexpressed PLAC8 was nucleated at the centrosome during mitosis, and therefore, PLAC8 overexpression might increase cell growth and migration (all p  < 0.05). The tumorigenic and invasive effects of PLAC8 on CRC cells were also confirmed in a xenograft mouse model. We further identified reduced levels of two butyrate-producing organisms, Butyricicoccus and Prevotella spp., in stools from CRC patients. We found that butyrate downregulated PLAC8 expression and induced apoptosis in PLAC8 -overexpressing cells. Our data suggests that PLAC8 gene and protein expression and dysbiosis of gut microflora, especially in butyrate-producing microorganisms, may be indicators of CRC progression., Competing Interests: The authors have declared no conflict of interest., (© 2019 THE AUTHORS. Published by Elsevier BV on behalf of Cairo University.)

Background: It has been proposed that 17-β-estradiol (E2) activates estrogen receptor and inhibits renal cell carcinoma (RCC) growth. In the present study we explored the role of E2 and ER in the regulation of RCC growth., Materials and Methods: The RCC cell line ACHN was treated by E2 combining with E2 antagonist Fulvestrant or ER knockdown, and cell growth was monitored. Quantitative phosphoproteomics was applied to study the E2 regulated non-genomic phosphorylation changes. Western blotting, immunofluorescence microscopy, and apoptosis assays were used for validation., Results: E2 induced ER-dependent growth inhibition in RCC cell lines. Quantitative phosphoproteomics revealed that E2 induced both apoptosis and autophagy. Cellular apoptosis was confirmed by altered mitochondrial membrane potential, and ER-dependent autophagosome formation was also found., Conclusion: Our data revealed the potential dual roles of E2 in regulating RCC growth via autophagy and apoptosis pathways., (Copyright© 2016, International Institute of Anticancer Research (Dr. John G. Delinasios), All rights reserved.)