Overexpression of βTrCP1 elicits cell death in cisplatin-induced senescent cells

TL;DR

Overexpression of βTrCP1 causes death in senescent cells after cisplatin treatment, offering a potential new target for cancer therapy.

Contribution

Identifies βTrCP1 as a novel target for senolytic drugs by revealing its role in inducing cell death in senescent tumor cells.

Findings

Lentiviral overexpression of βTrCP1 induces death in cisplatin-induced senescent cells.

βTrCP1 promotes proteasome-dependent degradation of p21 CIP1 via interaction with NPM1.

Retaining NPM1 in the nucleoli under senescent conditions leads to cell death.

Abstract

Senescence is a non-proliferative cellular state derived from aging or in response to exogenous insults, such as those that cause DNA damage. As a result of cancer treatments like cisplatin, certain tumor cells may undergo senescence. However, rather than being beneficial for patients, this is detrimental because these cells might proliferate again under specific conditions and, more importantly, because they synthesize and secrete molecules that promote the proliferation of nearby cells. Therefore, to achieve complete tumor remission, it is necessary to develop senolytic compounds to eliminate senescent cells. Here, we studied the role of βTrCP1 in cell proliferation and senescence and found that lentiviral overexpression of βTrCP1 induces the death of senescent cells obtained after cisplatin treatment in both two-dimensional cell cultures and tumorspheres. Mechanistically, we demonstrated that overexpression of βTrCP1 triggers proteasome-dependent degradation of p21 CIP1, allowing damaged cells to progress through the cell cycle and consequently die. Furthermore, we identified nucleophosmin 1 (NPM1) as the intermediary molecule involved in the effect of βTrCP1 on p21 CIP1. We determined that increased amounts of βTrCP1 partially retains NPM1 in the nucleoli, preventing it from associating with p21 CIP1, thus leaving it unprotected from degradation by the proteasome. These results have allowed us to discover a potential new target for senolytic drugs, as retaining NPM1 in the nucleoli under senescent conditions induces cell death.

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