Date of Award

13-3-2024

Document Type

Thesis

School

School of Chemical & Biotechnology

Programme

Ph.D.-Doctoral of Philosophy

Keywords

Triple Negative Breast Cancer, Centrosome Clustering, Survivin, Novel Indenone Derivative

Abstract

Triple-negative breast cancer (TNBC) confers considerable interventional challenge owing to its massive heterogeneity, aggression and metastatic prowess. These facets are attributed to chromosomal instability (CIN), a feature consequent to TNBC cell’s ability to harbor more than two centrosomes (supernumerary centrosomes; SNCs).

In principle, if a normal cell possesses SNCs, uneven pull forces are generated consequent to multipolar spindle, which activates cellular surveillance. This ensures error-free mitosis by either repairing the error or, in an irreparable condition, driving cells to death. This averts the possibility of aneuploidy (fundamental to tumorigenesis).

Unfortunately, TNBC cells, despite harboring SNCs, have devised a survival strategy to overcome death by clustering their SNCs into two opposite poles via centrosome clustering (CC). This mimicry not only circumvents surveillance but also enables cancer cells to thrive unperturbed. Therefore, CC inhibition might be an effective strategy to selectively kill TNBC cells.

However, the precise molecular mechanism that allows CC is hitherto unknown, and exploring the same might provide an insight into novel cellular targets for disrupting CC in TNBC. Herein, we attempted to identify a novel cellular target that governs CC in TNBC. We modulated the histone acetyltransferase activity of cAMP response element binding protein-binding protein (CBP), as only a handful of articles discuss its contribution to CIN. Inhibition of CBP by C646 attenuated the expression of proteins involved in the canonical NF-κB pathway (such as IKKα/β/γ, RelA).

On RelA inhibition, we noticed suppression of survivin (a cancer-specific target) in TNBC cells. Moreover, survivin attenuation declustered SNCs and induced multipolarity, which pushed TNBC cells to apoptosis. These findings were validated using a direct inhibitor of survivin, YM-155. YM-155 could kill TNBC cells by inducing spindle aberrations. Hence, we established survivin as a novel (functional) target in regulation of CC in TNBC cells.

We also identified a novel indenone derivative (nID) that could modulate the RelA-survivin functional axis and subsequently inhibit CC by inducing chromosome misalignment. Furthermore, we unraveled that in context to CC, a positive feedback loop between survivin and KIFC1 promotes cohesion of SNCs. Holistically, our research highlights the critical role of survivin in orchestrating CC in TNBC.

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