555 c-Rel suppression influences cell cycle regulation of human melanoma cells

Abstract

Melanoma progression is often associated with metastasis and chemoresistance, highlighting the continuous need for innovative therapeutic target identification. One typical hallmark of melanoma progression is disturbance of finely tuned cellular signaling mechanisms involving – among others - the constitutively expressed transcription factor NF-κB. The c-Rel subunit of NF-κB is a crucial player in epidermal homeostasis and is expressed in progressing melanoma and in some mitotic figures in situ. Down-regulation of c-Rel by siRNA resulted in reduced cell growth and modified cell cycle regulation in the four human melanoma cell lines A375, Lox, MV3 and Sk-Mel-23. In detail, the cell cycle was shifted towards the G2/M phase, and an induction of polyploid cells was observed in A375, Lox and MV3 cells. Furthermore, the three metastatic cell lines Lox, MV3 and Sk-Mel-23 showed significantly higher proportions of mitotic cell with altered mitotic spindle morphology, i.e. a monopolar spindle phenotype. Usually during mitosis, bipolar spindles are pulling the duplicated chromosomes towards opposite sites. Monopolar spindle formation therefore indicates defects during early mitosis possibly leading to aneuploidy, a hallmark of many cancer cells associated with chromosomal instability, or mitotic cell death. Our data suggest a tumor-promoting influence of c-Rel through affecting cell growth and cell cycle regulation with a putative direct or indirect impact on mechanisms influencing chromosomal instability and tumor progression.