Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

Abstract

Nearly a century ago, cell biologists postulated that the chromosomal aberrations blighting cancer cells might be caused by a mysterious organelle-the centrosome-that had only just been discovered. For years, however, this enigmatic structure was neglected in oncologic investigations and has only recently reemerged as a key suspect in tumorigenesis. A majority of cancer cells, unlike healthy cells, possess an amplified centrosome complement, which they manage to coalesce neatly at two spindle poles during mitosis. This clustering mechanism permits the cell to form a pseudo-bipolar mitotic spindle for segregation of sister chromatids. On rare occasions this mechanism fails, resulting in declustered centrosomes and the assembly of a multipolar spindle. Spindle multipolarity consigns the cell to an almost certain fate of mitotic arrest or death. The catastrophic nature of multipolarity has attracted efforts to develop drugs that can induce declustering in cancer cells. Such chemotherapeutics would theoretically spare healthy cells, whose normal centrosome complement should preclude multipolar spindle formation. In search of the 'Holy Grail' of nontoxic, cancer cell-selective, and superiorly efficacious chemotherapy, research is underway to elucidate the underpinnings of centrosome clustering mechanisms. Here, we detail the progress made towards that end, highlighting seminal work and suggesting directions for future research, aimed at demystifying this riddling cellular tactic and exploiting it for chemotherapeutic purposes. We also propose a model to highlight the integral role of microtubule dynamicity and the delicate balance of forces on which cancer cells rely for effective centrosome clustering. Finally, we provide insights regarding how perturbation of this balance may pave an inroad for inducing lethal centrosome dispersal and death selectively in cancer cells.

Cell Death Associated with Abnormal Mitosis Observed by Confocal Imaging in Live Cancer Cells

“…Bipolar centrosome assembly is crucial for bipolar spindle formation in mitosis 4,5 . Therefore, cells with more than two centrosomes have developed a scarcely understood molecular mechanism, clustering their extra centrosomes at two poles [4][5][6][7][8][9] . Failure of bipolar assembly of their centrosomes may cause multipolar distorted spindles and aberrant chromosomes segregation that arrests the cell-cycle in G2/M arrest, 4,5 .…”

Integrin-linked kinase regulates senescence in an Rb-dependent manner in cancer cell lines

“…Centrosome clustering is an essential mechanism for the survival of cancer cells [34][35][36] permitting cells with an amplified number of centrosomes to divide in a pseudo-bipolar fashion. Should this clustering fail, spindle multipolarity results, predisposing the cell to either mitotic arrest or death.…”

Centrosome Clustering in the Development of Bovine Binucleate Trophoblast Giant Cells

“…The supernumerous centrosomes can form multiple spindles poles. Such multipolar mitoses would in most cases lead to highly aneuploidy nonviable daughter cells [Ogden et al, 2012;McGee, 2015]. To avoid this, most polyploid cancer cells cluster the amplified centrosomes together, so that the cells have a "pseudo-bipolar" spindle during mitosis.…”

“…mor therapies [Ogden et al, 2012]. In normal diploid cells, the single centrosome duplicates before mitosis and during mitosis the 2 centrosomes form the 2 spindle poles [Firat-Karalar and Stearns, 2014].…”