Abstract
Cell division cycle 6 (Cdc6) plays key roles in regulating DNA replication, and activation and maintenance of cell cycle check points. In addition, Cdc6 exerts oncogenic properties via genomic instability associated with incomplete DNA replication. This study aimed to examine the effects of Cdc6 on pancreatic cancer (PC) cells. Our results showed that Cdc6 expression was higher in clinical PC specimens (based on analysis of the GEPIA database) and cell lines, and the high Cdc6 expression was associated with poorer survival in The Cancer Genome Atlas-PC cohort. In addition, Cdc6-depleted PC cells significantly inhibited cell proliferation and colony formation, delayed G2/M cell cycle progression, and increased expression of p-histone H3 and cyclin A2 levels. These observations could be explained by Cdc6 depletion leading to multipolar and split spindles via centrosome amplification and microtubule disorganization which eventually increases chromosome missegregation. Furthermore, Cdc6-depleted PC cells showed significantly increased apoptosis, which was consistent with increased caspase-9 and caspase-3 activation. Collectively, our results demonstrated that Cdc6-depleted PC cells are arrested in mitosis and eventually undergo cell death by induced multipolar spindles, centrosome aberrations, microtubule disorganization, and chromosome instability. In conclusion, Cdc6 may be a potential biomarker and therapeutic target for PC.
Highlights
Cell division cycle 6 (Cdc6) plays key roles in regulating DNA replication, and activation and maintenance of cell cycle check points
Our results showed that Cdc[6] mRNA levels were significantly higher in pancreatic cancer (PC) tissues (n = 179) than normal tissues (n = 171) from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) data (Fig. 1A)
We analyzed the expression of Cdc[6] in PC cell lines by western blot analysis, and observed that Cdc[6] was up-regulated in various PC cell lines including AsPC-1, PANC-1, MIA PaCa-2, and Capan-1 cells compared to human umbilical vein
Summary
Cell division cycle 6 (Cdc6) plays key roles in regulating DNA replication, and activation and maintenance of cell cycle check points. Cdc6-depleted PC cells significantly inhibited cell proliferation and colony formation, delayed G2/M cell cycle progression, and increased expression of p-histone H3 and cyclin A2 levels These observations could be explained by Cdc[6] depletion leading to multipolar and split spindles via centrosome amplification and microtubule disorganization which eventually increases chromosome missegregation. Our results demonstrated that Cdc6-depleted PC cells are arrested in mitosis and eventually undergo cell death by induced multipolar spindles, centrosome aberrations, microtubule disorganization, and chromosome instability. Cell division requires the precise coordination and execution of several events in the cell cycle, including centrosome duplication, DNA replication, mitotic spindle assembly, chromosome segregation, and cytokinesis. Cell division cycle 6 (Cdc6) is a key component of the pre-replication complex (pre-RC) that initiates DNA replication and plays important roles in the activation and maintenance of cell cycle checkpoint mechanisms. We showed that Cdc[6] may be a potential anticancer target and may help to understand the mechanism of PC progression
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