Abstract
Colon cancer is one of the leading causes of cancer-related death worldwide and the therapy with 5-fluorouracil (5-FU) is mainly limited due to resistance. Recently, we have demonstrated that nucleolar stress upon 5-FU treatment leads to the activation of ribosome-free rpL3 (L3) as proapoptotic factor. In this study, we analyzed L3 expression profile in colon cancer tissues and demonstrated that L3 mRNA amount decreased with malignant progression and the intensity of its expression was inversely related to tumor grade and Bcl-2/Bax ratio. With the aim to develop a combined therapy of 5-FU plus plasmid encoding L3 (pL3), we firstly assessed the potentiation of the cytotoxic effect of 5-FU on colon cancer cells by L3. Next, 10 μM 5-FU and 2 μg of pL3 were encapsulated in biocompatible nanoparticles (NPs) chemically conjugated with HA to achieve active tumor-targeting ability in CD44 overexpressing cancer cells. We showed the specific intracellular accumulation of NPs in cells and a sustained release for 5-FU and L3. Analysis of cytotoxicity and apoptotic induction potential of combined NPs clearly showed that the 5-FU plus L3 were more effective in inducing apoptosis than 5-FU or L3 alone. Furthermore, we show that the cancer-specific chemosensitizer effect of combined NPs may be dependent on L3 ability to affect 5-FU efflux by controlling P-gp (P-glycoprotein) expression. These results led us to propose a novel combined therapy with the use of 5-FU plus L3 in order to establish individualized therapy by examining L3 profiles in tumors to yield a better clinical outcomes.
Highlights
IntroductionRibosomal proteins (r-proteins) in addition to the role as components of translation machinery, exert a variety of extra-ribosomal functions [1,2,3,4]
In eukaryotes, ribosomal proteins (r-proteins) in addition to the role as components of translation machinery, exert a variety of extra-ribosomal functions [1,2,3,4].These extraribosomal activities include DNA replication transcription and repair; RNA splicing and modification; cell growth and proliferation; regulation of apoptosis and cellular transformation
We demonstrate that L3 expression in colon tumor tissues is downregulated; L3 mRNA decrease associated with malignance progression and tumor grade and was inversely proportional to the ratio Bcl-2/Bax; L3 overexpression in 5-FU treated colon cancer cells decreased clonogenic potency, cell migration and cell viability, and stimulated apoptotic cell death by inducing late apoptosis
Summary
Ribosomal proteins (r-proteins) in addition to the role as components of translation machinery, exert a variety of extra-ribosomal functions [1,2,3,4]. These extraribosomal activities include DNA replication transcription and repair; RNA splicing and modification; cell growth and proliferation; regulation of apoptosis and cellular transformation. Several r-proteins represent additional important component of p53 autoregulatory feedback loop and are shown to activate p53 and trigger cell cycle arrest and apoptosis [7, 8]. Many r-proteins can themselves function as tumor suppressors
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