Centrosome – a promising anti-cancer target

Abstract

The centrosome, an organelle discovered >100 years ago, is the main microtubule-organizing center in mammalian organisms. The centrosome is composed of a pair of centrioles surrounded by the pericentriolar material (PMC) and plays a major role in the regulation of cell cycle transitions (G1-S, G2-M, and metaphase-anaphase), ensuring the normality of cell division. Hundreds of proteins found in the centrosome exert a variety of roles, including microtubule dynamics, nucleation, and kinetochore–microtubule attachments that allow correct chromosome alignment and segregation. Errors in these processes lead to structural (shape, size, number, position, and composition), functional (abnormal microtubule nucleation and disorganized spindles), and numerical (centrosome amplification [CA]) centrosome aberrations causing aneuploidy and genomic instability. Compelling data demonstrate that centrosomes are implicated in cancer, because there are important oncogenic and tumor suppressor proteins that are localized in this organelle and drive centrosome aberrations. Centrosome defects have been found in pre-neoplasias and tumors from breast, ovaries, prostate, head and neck, lung, liver, and bladder among many others. Several drugs/compounds against centrosomal proteins have shown promising results. Other drugs have higher toxicity with modest or no benefits, and there are more recently developed agents being tested in clinical trials. All of this emerging evidence suggests that targeting centrosome aberrations may be a future avenue for therapeutic intervention in cancer research.

Genetic variation and radiation quality impact cancer promoting cellular phenotypes in response to HZE exposure

“…Our main goal was to test whether genetic variation confers increased risk for the development of cancer predisposing phenotypes post exposure to HZE radiation. We chose to study centrosome aberrations as our surrogate end point of cancer risk, as it has been well documented that aberrations in centrosome number can disrupt tissue architecture and genomic instability; the two main hallmarks of carcinogenesis (Nigg, 2006;Rivera-Rivera & Saavedra, 2016). We and others have also shown that centrosome defects increase with simple and complex damage (Sato et al, 1983;Sudo et al, 2008, Sridharan et al, 2017 and can sensitively differentiate between radiation and age dependent effects (Sridharan et al, 2017).…”

Centrosome aberrations and chromosome instability contribute to tumorigenesis and intra-tumor heterogeneity

“…Given the numerous mechanisms attributed to chromosomal instability, several approaches have been proposed to target chromosome instability in cancer. One approach is to target centrosome-associated proteins that regulate microtubule dynamics and the SAC to prevent centrosome amplification, thus preventing chromosome instability [ 87 , 189 , 190 ] . The Cdk4/Cdk6 inhibitor Palbociclib (PD-0332991) in combination with the aromatase inhibitor letrozole has greatly improved the outcomes of ER + , Her2 − advanced breast cancer patients [ 191 , 192 ] .…”

“…In fact, Palbociclib is ineffective in basal breast cancer cells (the subtype with a higher degree of chromosome instability), and patients are harboring alterations in the Rb/E2F pathway [ 193 , 194 ] . Nevertheless, several inhibitors targeting polo-like kinases (Plks) and Aurora kinases (AURKs) have been tested in pre-clinical and clinical trials with mixed outcomes, and this has been extensively discussed elsewhere [ 189 ] . Notably, the inhibitor MLN8237 (Asertib) that targets AURKs exhibited efficacy for several solid tumors and T-cell lymphoma, but not acute myeloid leukemia [ 195 , 196 ] .…”

“…Notably, the inhibitor MLN8237 (Asertib) that targets AURKs exhibited efficacy for several solid tumors and T-cell lymphoma, but not acute myeloid leukemia [ 195 , 196 ] . The opposite was observed for the selective inhibitor of AURKB, AZD1152 (Barasertib) [ 189 ] .…”

Regulation of the cell cycle and centrosome biology by deubiquitylases

“…Duplication of the single G 1 centrosome begins at the G 1 /S transition and is completed during S-phase, so that two centrosomes are present in G 2 . These facilitate bipolar spindle formation at metaphase and are then segregated, one into each daughter cell, during cytokinesis [ 53 , 54 ]. Key to centrosome replication is centriole duplication, as the pre-existing mother centriole duplicates itself to form a daughter centriole.…”