Oncotarget

Research Papers:

5-FU targets rpL3 to induce mitochondrial apoptosis via cystathionine-β-synthase in colon cancer cells lacking p53

Valentina Pagliara, Assunta Saide, Emma Mitidieri, Roberta d’Emmanuele di Villa Bianca, Raffaella Sorrentino, Giulia Russo and Annapina Russo _

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Oncotarget. 2016; 7:50333-50348. https://doi.org/10.18632/oncotarget.10385

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Abstract

Valentina Pagliara1, Assunta Saide1, Emma Mitidieri1, Roberta d’Emmanuele di Villa Bianca1, Raffaella Sorrentino1, Giulia Russo1, Annapina Russo1

1Department of Pharmacy, University of Naples “Federico II”, 80131 Naples, Italy

Correspondence to:

Annapina Russo, email: annapina.russo@unina.it

Keywords: nucleolar stress, p53, CBS, colon cancer, apoptosis

Received: April 29, 2016    Accepted: June 18, 2016    Published: July 2, 2016

ABSTRACT

Recent findings revealed in cancer cells novel stress response pathways, which in response to many chemotherapeutic drugs causing nucleolar stress, will function independently from tumor protein p53 (p53) and still lead to cell cycle arrest and/or apoptosis. Since it is known that most cancers lack functional p53, it is of great interest to explore these emerging molecular mechanisms. Here, we demonstrate that nucleolar stress induced by 5-fluorouracil (5-FU) in colon cancer cells devoid of p53 leads to the activation of ribosomal protein L3 (rpL3) as proapoptotic factor. rpL3, as ribosome-free form, is a negative regulator of cystathionine-β-synthase (CBS) expression at transcriptional level through a molecular mechanism involving Sp1. The rpL3-CBS association affects CBS stability and, in addition, can trigger CBS translocation into mitochondria. Consequently apoptosis will be induced through the mitochondrial apoptotic cell death pathway characterized by an increased ratio of Bax to Bcl-2, cytochrome c release and subsequent caspase activation. It is noteworthy that silencing of CBS is associated to a strong increase of 5-FU-mediated inhibition of cell migration and proliferation. These data reveal a novel mechanism to accomplish p53-independent apoptosis and suggest a potential therapeutic approach aimed at upregulating rpL3 for treating cancers lacking p53.


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PII: 10385