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Abstract Abnormal lipid metabolism and lipid accumulation are characteristic hallmarks of renal cell carcinoma (RCC). While there is prior evidence closely linking such lipid accumulation within RCC cells and consequent tumorigenesis, the mechanisms underlying this process remain incompletely understood. In this study, a series of bioinformatics analyses were initially performed by screening RCC databases and gene sets, ultimately leading to the identification of TRIB3 as an oncogene that functions as a central regulator of lipid metabolism. TRIB3 overexpression was observed in both RCC patient tumor tissues and cell lines, and this upregulation was correlated with a worse RCC patient prognosis. When TRIB3 was knocked down, this resulted in a reduction in lipid accumulation and the consequent induction of endoplasmic reticulum (ER) stress-related apoptotic cell death. At the molecular level, interactions between TRIB3 and PLIN2 were found to abrogate TEB4-mediated PLIN2 ubiquitination and consequent degradation, thus maintaining higher PLIN2 expression levels. This simultaneously helps facilitate the accumulation of lipids while preserving ER homeostasis, thus driving accelerated RCC tumor progression. This TRIB3-PLIN2 axis thus represents a promising new target for efforts to treat RCC.

Abstract Metabolic dysfunction is seen in cancer cells where increased glycolysis provides energy for growth. Circular RNAs (circRNAs) are thought to assist in glucose metabolism and the switch to glycolysis. Through screening, we found that circVAMP3 was necessary for both glycolytic and proliferative activities in renal cell carcinoma (RCC). Furthermore, circVAMP3 expression was elevated in RCC patients in correspondence with TNM stage. Mechanistically, circVAMP3 was observed to interact directly with lactate dehydrogenase A (LDHA) and modulate its activity. The circVAMP3–LDHA interaction facilitated LDHA phosphorylation at tyrosine 10 (Y10) catalyzed by the upstream kinase fibroblast growth factor receptor type 1 (FGFR1). Therefore, this study reveals a novel molecular mechanism by which circVAMP3 promotes glycolysis and proliferation through regulating the enzymatic activity of glycolytic enzyme, suggesting that circVAMP3 may represent an RCC biomarker and treatment target.

Abstract Background Cancer cells prefer utilizing aerobic glycolysis in order to exacerbate tumor mass and maintain un-regulated proliferative rates. As a key glycolytic activator, phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) has been implicated in multiple tumor type progression. However, the specific function and clinical significance of PFKFB3 in renal cell carcinoma (RCC) are yet not clarified. This investigation assessed PFKFB3 roles in RCC. Methods PFKFB3 expression levels were analyzed in clear cell renal cell carcinoma (ccRCC) tissues, together with its relationship with clinical characteristics of ccRCC. Real-time PCR and Western blot assays were employed for determining PFKFB3 expression in different RCC cell lines. Furthermore, we determined the glycolytic activity by glucose uptake, lactate secretion assay and ECAR analysis. CCK-8 assay, clone formation, flow cytometry and EdU assessments were performed for monitoring tumor proliferative capacity and cell-cycle distribution. Furthermore, a murine xenograft model was employed for investigating the effect of PFKFB3 on tumor growth in vivo. Results PFKFB3 was significantly up-regulated in RCC specimens and cell lines in comparison to normal control. Overexpression of PFKFB3 was directly correlated to later TNM stages, thus becoming a robust prognostic biomarker for ccRCC cases. Furthermore, PFKFB3 knockdown suppressed cell glycolysis, proliferative rate and cell-cycle G1/S conversion in RCC cells. Importantly, in vivo experiments confirmed that PFKFB3 knockdown delayed tumor growth derived from the ACHN cell line. Conclusions Such results suggest that PFKFB3 is a key molecular player in RCC progression via mediating glycolysis / proliferation and provides a potential therapeutic target against RCC.

Breast cancer is the most prevalent tumor in women worldwide and about 70% patients are estrogen receptor positive. In these cancer patients, resistance to the anticancer estrogen receptor antagonist tamoxifen emerges to be a major clinical obstacle. Peptidyl-prolyl isomerase Pin1 is prominently overexpressed in breast cancer and involves in tamoxifen-resistance. Here, we explore the mechanism and effect of targeting Pin1 using its chemical inhibitor all-trans retinoic acid (ATRA) in the treatment of tamoxifen-resistant breast cancer. We found that Pin1 was up-regulated in tamoxifen-resistant human breast cancer cell lines and tumor tissues from relapsed patients. Pin1 overexpression increased the phosphorylation of ERα on S118 and stabilized ERα protein. ATRA treatment, resembling the effect of Pin1 knockdown, promoted ERα degradation in tamoxifen-resistant cells. Moreover, ATRA or Pin1 knockdown decreased the activation of ERK1/2 and AKT pathways. ATRA also reduced the nuclear expression and transcriptional activity of ERα. Importantly, ATRA inhibited cell viability and proliferation of tamoxifen-resistant human breast cancer cells in vitro. Slow-releasing ATRA tablets reduced the growth of tamoxifen-resistant human breast cancer xenografts in vivo. In conclusion, ATRA-induced Pin1 ablation inhibits tamoxifen-resistant breast cancer growth by suppressing multifactorial mechanisms of tamoxifen resistance simultaneously, which demonstrates an attractive strategy for treating aggressive and endocrine-resistant tumors.