Ara-c induces cell cycle G1/S arrest by inducing upregulation of the INK4 family gene or directly inhibiting the formation of the cell cycle-dependent complex CDK4/cyclin D1

Abstract

Cytosine arabinoside (Ara-c) is a pyrimidine anti-metabolite that is capable of interfering with cellular proliferation by inhibiting DNA synthesis. Each inhibitor of cyclin-dependent kinase 4 (INK4) family member has the ability to bind to cyclin-dependent kinase 4 (CDK4) and inhibit the formation of the cell cycle-dependent CDK4/cyclin D1 complex, subsequently leading to cell cycle arrest in the G1/S phase. In this study, the expression of INK4 family genes in kidney cancer and the impact of these genes on patient prognosis were examined. Additionally, the effects of INK4 family genes and Ara-c on cell proliferation and tumor formation and development were examined. Finally, a potential association between Ara-c-induced cell cycle arrest and INK4-associated gene expression was evaluated. An upregulation of INK4 family genes was found to be positively correlated with the prognosis of patients with kidney cancer. Both the INK4 family genes and Arac were shown to induce cell cycle arrest and inhibit tumor formation and development. Moreover, Ara-c-induced cell cycle arrest was found to be associated with an Ara-c-induced upregulation of INK4 family gene expression, which ultimately inhibited the formation of the CDK4/cyclin D1 complex. These findings suggested that an upregulation of INK4 family genes has a positive effect on kidney cancer prognosis and can inhibit the formation and development of tumors. Moreover, Ara-c was shown to promote the upregulation of INK4 family genes, at the same time, Ara-c could directly regulate the cell cycle-dependent genes CDK4 and cyclin D1 (CCND1), independent of the INK4 family genes.

The cancer-testis gene, <i>MEIOB</i>, sensitizes triple-negative breast cancer to PARP1 inhibitors by inducing homologous recombination deficiency

“…Our results further showed that the overexpression of MEIOB in SUM1315MO2 cells resulted in cell cycle arrest at the G1 phase, which indicated that MEIOB might be absent from homologous recombination while being involved in the non-homologous end joining (NHEJ) repair process ( Figure 3C ). As reported in past studies, CDK4 and CDK2 are necessary for cells to enter the G1 phase from the G0 phase 30 . In MEIOB-overexpressing SUM1315MO2 cells, we observed increased expressions of CDK2 and CDK4 , which further confirmed that MEIOB induced SUM1315MO2 cells to maintain G1/G0 phase arrest ( Figure 3D ).…”

GLI1 reduces drug sensitivity by regulating cell cycle through PI3K/AKT/GSK3/CDK pathway in acute myeloid leukemia

“…S2B, C ). Ara-c, a nucleoside analog, causes S phase cell cycle arrest, inhibits DNA polymerase, and directly regulates the cell cycle genes CDK4 and cyclin D1 (CCND1), subsequently leading to cell cycle arrest in the G1/S phase 32 . Therefore, the synergism between GLI1 knockdown and Ara-c is likely achieved by targeting different phases of the cell cycle.…”

Circ-Smad5 retards the G1/S transition of cell cycle via inhibiting the activity of wnt/lef/cyclind1 signaling in JB6 cells

“…The activity of CDKs depends on cyclins. Cyclin D1 is a major cyclin that regulates the cell cycle transition from G1 to S. 25 , 26 The expression of cyclin D1 was higher in the sh-circ-Smad5 group than in the control group. These data demonstrate that circ-Smad5 may regulate the proliferation of JB6 cells by regulating the expression cyclin D1.…”