Abstract
Centrosome amplification (CA) and resultant chromosomal instability have long been associated with tumorigenesis. However, exacerbation of CA and relentless centrosome declustering engender robust spindle multipolarity (SM) during mitosis and may induce cell death. Recently, we demonstrated that a noscapinoid member, reduced bromonoscapine, (S)-3-(R)-9-bromo-5-(4,5-dimethoxy-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo-[4,5-g]isoquinoline (Red-Br-nos), induces reactive oxygen species (ROS)-mediated autophagy and caspase-independent death in prostate cancer PC-3 cells. Herein, we show that Red-Br-nos induces ROS-dependent DNA damage that resulted in high-grade CA and SM in PC-3 cells. Unlike doxorubicin, which causes double-stranded DNA breaks and chronic G2 arrest accompanied by ‘templated' CA, Red-Br-nos-mediated DNA damage elicits de novo CA during a transient S/G2 stall, followed by checkpoint abrogation and mitotic entry to form aberrant mitotic figures with supernumerary spindle poles. Attenuation of multipolar phenotype in the presence of tiron, a ROS inhibitor, indicated that ROS-mediated DNA damage was partly responsible for driving CA and SM. Although a few cells (∼5%) yielded to aberrant cytokinesis following an ‘anaphase catastrophe', most mitotically arrested cells (∼70%) succumbed to ‘metaphase catastrophe,' which was caspase-independent. This report is the first documentation of rapid de novo centrosome formation in the presence of parent centrosome by a noscapinoid family member, which triggers death-inducing SM via a unique mechanism that distinguishes it from other ROS-inducers, conventional DNA-damaging agents, as well as other microtubule-binding drugs.
Highlights
This has been recently named ‘anaphase catastrophe,’ a phenomenon that can be pharmacologically induced for selective targeting of cancer cells.[12]
centrosome amplification (CA) allows maintenance of ‘optimal’ aneuploidy to facilitate tumorigenesis by selection of karyotypes that offer growth advantage,[38] exacerbation of CA may be detrimental to cancer cell survival, serving as a favorable chemotherapeutic approach
Our current study demonstrates for the first time a link between Red-Br-nos-induced early reactive oxygen species (ROS) production and DNA damage with CA-induced spindle multipolarity (SM), which formed the basis of substantial cell death via ‘metaphase catastrophe’ (Figure 7)
Summary
This has been recently named ‘anaphase catastrophe,’ a phenomenon that can be pharmacologically induced for selective targeting of cancer cells.[12]. Our data demonstrate that Red-Br-nos induces ROSdependent DNA damage, which causes de novo CA associated with increased cdk[2] activity and enhanced polo-like kinase-4 (PLK4) expression.
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