Identification of Target Proteins for Promoting Nuclear Envelope Rupture in Cancer Cells

Abstract

The nuclear envelope separates and protects DNA from the cytoplasm. In cancer cells, frequent nuclear morphological abnormalities and transient rupture of the nuclear membrane promote DNA damage and cancer malignancy. However, nuclear envelope instability, acting as a tumor-promotion factor, can be viewed as a fatal weakness of cancer cells. Although the exact mechanism is not clear, it is known that the loss of the tumor suppressor gene TP53 is involved in nuclear envelope instability in cancer cells. In this study, we demonstrate that the inhibition of NUP93, which is a subunit of the nuclear pore complex, induces cell death by enhancing nuclear envelope instability. The RNA interference (RNAi) inhibiting NUP93 expression in the human cell line RPE1 caused nuclear envelope rupture, and DNA damage, leading to cell death. Under the condition in which the tumor suppressor gene TP53 was simultaneously suppressed with NUP93, nuclear envelope rupture and DNA damage were significantly increased. Conversely, cell death was slightly decreased. The decrease in cell death may be ascribed to the fact that TP53 is involved in the induction of apoptosis by DNA damage. We speculate that amplification of nuclear envelope instability may induce cancer cell-specific synthetic lethality in the context of TP53-independent nuclear envelope instability. Moreover, our results suggest that nuclear pore proteins can be promising targets for the development of synthetic lethal anticancer drugs.