Apoptosis is a programmed cell death that efficiently removes damaged cells to maintain tissue homeostasis. Defect in apoptotic machinery can lead to tumor development, progression, and resistance to chemotherapy. PUMA (p53 upregulated modulator of apoptosis) and BAX (BCL2-associated X protein) are among the most well-known inducers of apoptosis. It has been reported that expression levels of BAX and PUMA are controlled at the posttranslational level by phosphorylation. However, the posttranslational regulation of these proapoptotic proteins remains largely unexplored. In this study, using biochemical, molecular biology, flow cytometric, and immunohistochemistry techniques, we show that PUMA and BAX are the direct target of the F-box protein FBXL20, which restricts their cellular levels. FBXL20 directs the proteasomal degradation of PUMA and BAX in a protein kinase AKT1-dependent manner to promote cancer cell proliferation and tumor growth. Interestingly, inactivation of AKT1 results in activation of another protein kinase GSK3α/β, which facilitates the proteasomal degradation of FBXL20 by another F-box protein, FBXO31. Thus, a switch between two signaling kinases AKT1 and GSK3α/β modulates the functional activity of these proapoptotic regulators, thereby determining cell survival or death. RNAi-mediated ablation of FBXL20 results in increased levels of PUMA as well as BAX, which further enhances the sensitivity of cancer cells to chemotherapeutic drugs. We showed that high level expression of FBXL20 in cancer cells reduces therapeutic drug-induced apoptosis and promotes chemoresistance. Overall, this study highlights the importance of targeting FBXL20 in cancers in conjunction with chemotherapy and may represent a promising anticancer strategy to overcome chemoresistance.
Introduction and Aim: Plants are the most accessible and convenient source of lectins. Artocarpus altilis is a Moraceae plant utilized for its latex. The anti-proliferative, nematicidal, and insecticidal effects of this plant latex are unknown. The current study evaluates the antiproliferative, nematicidal, and insecticidal activity of pure AaLL on Triple Negative Breast Cancer cells, Meloidogyne incognita, and Spodoptera frugiperda, respectively. Materials and Methods: To assess AaLL's antiproliferative activity against MDA-MB-231, MTT and wound healing experiments were performed. Using juvenile mortality and feeding assays, the in vitro nematicidal and insecticidal activity against Meloidogyne incognita and Spodoptera frugiperda were evaluated. Results: The MTT experiment demonstrated that 5.4µg/ml AaLL effectively inhibited MDA-MB-231 growth by 50% compared to the control. Even at 40µg/ml, AaLL had no cytotoxic effects on NIH3T3 fibroblast cells. AaLL significantly reduced cell migration, with the wound area remaining at 41.95 percent as opposed to 4.57 percent in the control group. In vitro results on J2s exposed to AaLL for 72 hours demonstrated a death rate of 52% at a concentration of 30µg/ml. After 24 hours of incubation with 400µg/ml lectin, the insecticidal tests reveal that AaLL considerably reduces the weight of larvae. After 48 hours, a lectin concentration of 0.04% caused 69.44% larval death. Conclusion: This is the first report demonstrating the latex lectin from Artocarpus altilis's anti-proliferation, anti-migration, nematicidal, and insecticidal properties. Further research will be done on the signaling pathways and mechanism of action linked to these features.
Prostate cancer (PCa) progresses from a hormone-sensitive, androgen-dependent to a hormone-refractory, androgen-independent metastatic phenotype. Among the many genes implicated, ANXA2, a calcium-dependent phospholipid binding protein, has been found to have a critical role in the progression of PCa into more invasive metastatic phenotype. However, the molecular mechanisms underlying the absence of ANXA2 in early PCa and its recurrence in advanced stage are yet unknown. Moreover, recent studies have observed the deregulation of microRNAs (miRNAs) are involved in the development and progression of PCa. In this study, we found the down-regulation of miR-936 in metastatic PCa wherein its target ANXA2 was overexpressed. Subsequently, it has been shown that the downregulation of miRNA biogenesis by siRNA treatment in ANXA2-null LNCaP cells could induce the expression of ANXA2, indicating the miRNA mediated regulation of ANXA2 expression. Additionally, we demonstrate that miR-936 regulates ANXA2 expression by direct interaction at coding as well as 3′UTR region of ANXA2 mRNA by luciferase reporter assay. Furthermore, the overexpression of miR-936 suppresses the cell proliferation, cell cycle progression, cell migration, and invasion abilities of metastatic PCa PC-3 cells in vitro and tumor forming ability in vivo. These results indicate that miR-936 have tumor suppressor properties by regulating the over expression of ANXA2 in hormone-independent metastatic PCa. Moreover, our results suggest that this tumor suppressor miR-936 could be developed as a targeted therapeutic molecule for metastatic PCa control and to improve the prognosis in PCa patients.
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