The functions of the proto-oncoprotein c-Myc and the tumor suppressor p53 in controlling cell survival and proliferation are inextricably linked as “Yin and Yang” partners in normal cells to maintain tissue homeostasis: c-Myc induces the expression of ARF tumor suppressor (p14ARF in human and p19ARF in mouse) that binds to and inhibits mouse double minute 2 homolog (MDM2) leading to p53 activation, whereas p53 suppresses c-Myc through a combination of mechanisms involving transcriptional inactivation and microRNA-mediated repression. Nonetheless, the regulatory interactions between c-Myc and p53 are not retained by cancer cells as is evident from the often-imbalanced expression of c-Myc over wildtype p53. Although p53 repression in cancer cells is frequently associated with the loss of ARF, we disclose here an alternate mechanism whereby c-Myc inactivates p53 through the actions of the c-Myc-Inducible Long noncoding RNA Inactivating P53 (MILIP). MILIP functions to promote p53 polyubiquitination and turnover by reducing p53 SUMOylation through suppressing tripartite-motif family-like 2 (TRIML2). MILIP upregulation is observed amongst diverse cancer types and is shown to support cell survival, division and tumourigenicity. Thus our results uncover an inhibitory axis targeting p53 through a pan-cancer expressed RNA accomplice that links c-Myc to suppression of p53.
Aim: To optimize formulation methods for loading gemcitabine (GEM), the main drug against pancreatic cancer, into albumin nanoparticles for extended blood circulation and improved efficacy. Methods: GEM was loaded into two sizes of disolvation-crosslinked bovine serum albumin nanoparticles, with a mean diameter of 109.7 nm and 405.6 nm, respectively, by co-precipitation (the direct method) and follow-up adsorption (the indirect method). The antitumor activities of the two nanoparticulate formulations, were evaluated according to their anti-proliferative effects on the human pancreatic cell line BXPC-3, which were assessed using the MTT assay. Results: The two nanoparticulate formulations, created by direct co-precipitation and indirect adsorption, possessed smooth surfaces and high drug loading efficiencies, 83% and 93% at 11% and 13% drug loading, respectively. The two formulations released GEM for 8 and 12 h, respectively, and significantly improved anti-BXPC-3 proliferation effects, as compared with the GEM solution and the drugfree albumin particles. Conclusion: Co-precipitating and adsorbing GEM into albumin particles resulted in sustained-release nanoparticulate formulations with improved antitumor cytotoxicity. The result suggests that this is a useful formulation strategy for improving the antitumor efficacy of GEM.
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