Therapeutic Approaches Targeting Nucleolus in Cancer

Abstract

The nucleolus is a distinct sub-cellular compartment structure in the nucleus. First observed more than 200 years ago, the nucleolus is detectable by microscopy in eukaryotic cells and visible during the interphase as a sub-nuclear structure immersed in the nucleoplasm, from which it is not separated from any membrane. A huge number of studies, spanning over a century, have identified ribosome biogenesis as the main function of the nucleolus. Recently, novel functions, independent from ribosome biogenesis, have been proposed by several proteomic, genomic, and functional studies. Several works have confirmed the non-canonical role for nucleoli in regulating important cellular processes including genome stability, cell-cycle control, the cellular senescence, stress responses, and biogenesis of ribonucleoprotein particles (RNPs). Many authors have shown that both canonical and non-canonical functions of the nucleolus are associated with several cancer-related processes. The association between the nucleolus and cancer, first proposed by cytological and histopathological studies showing that the number and shape of nucleoli are commonly altered in almost any type of cancer, has been confirmed at the molecular level by several authors who demonstrated that numerous mechanisms occurring in the nucleolus are altered in tumors. Recently, therapeutic approaches targeting the nucleolus in cancer have started to be considered as an emerging “hallmark” of cancer and several therapeutic interventions have been developed. This review proposes an up-to-date overview of available strategies targeting the nucleolus, focusing on novel targeted therapeutic approaches. Finally, a target-based classification of currently available treatment will be proposed.

uL3 Mediated Nucleolar Stress Pathway as a New Mechanism of Action of Antiproliferative G-quadruplex TBA Derivatives in Colon Cancer Cells

“…Recent data indicate that cancer cells exhibit upregulation of ribosome biogenesis and result in a high sensitivity to drugs that activate the nucleolar stress response [22]. In this context, our results may have a significant value in the development of new targeted anticancer therapies for colorectal tumors lacking p53, which are often resistant to current therapies and have a poor prognosis.…”

“…As shown in Figure 3A, in the presence of uL3, the treatment of HCT 116 p53−/− cells with LQ1 caused a significant increase of uL3, uL5, uL11, and uL18 mRNA levels and a decrease of B23/NPM transcript levels. The observed alteration in the expression of these proteins is a hallmark of the activation of nucleolar stress [22]. When uL3 expression was switched off, LQ1 failed to exert its effects on the expression of tested ribosomal and nucleolar proteins ( Figure 3B).…”

“…Ribosomal proteins (r-proteins) are nucleolar proteins that, in addition to their role in ribosome biogenesis, show extra-ribosomal functions, some of which affect cancer biology [20,21]. uL3, formerly named rpL3, belongs to this subset of r-proteins, and, as extra-ribosomal player, is involved in a number of cellular events activated in response to cell stressors that trigger the so-called "nucleolar stress response" [21][22][23][24]. The expression levels of uL3 require specific regulatory strategies, including the association of alternative splicing and nonsense-mediated mRNA decay (AS-NMD) [25].…”

“…The activity of ribosome free uL3 has been intensively investigated by some of us. A key role of ribosome-free uL3 is to arrest cell cycle progression and/or to induce apoptosis in response to different conventionally used chemotherapeutic drugs, interfering with ribosome biogenesis, such as Actinomycin D, 5-fluorouracile, Oxaliplatin, and Niclosamide [21,22,[24][25][26][27].…”

Role of uL3 in the Crosstalk between Nucleolar Stress and Autophagy in Colon Cancer Cells

“…It has been demonstrated that most chemotherapeutic drugs used in colon cancer are able to activate the so-called nucleolar stress response which in turn causes translocation of ribosomal proteins (r-proteins) as ribosome free proteins from the nucleolus to the nucleoplasm [4,5]. The nucleoplasmatic accumulation of these proteins is associated, through mechanisms dependent or independent of p53, to cell cycle arrest and/or apoptosis [4].…”