High expression of PSF1 promotes drug resistance and cell cycle transit in leukemia cells

Abstract

Escape of cancer cells from chemotherapy is a problem in the management of cancer patients. Research on chemotherapy resistance has mainly focused on the heterogeneity of cancer cells, multiple gene mutations, and quiescence of malignant cancer cells. However, some studies have indicated that interactions between cancer cells and vascular cells promote resistance to chemotherapy. Here, we established mouse leukemia models using the cell lines THP‐1 or MEG‐1. These were derived from acute and chronic myeloid leukemias, respectively, and highly expressed DNA replication factor PSF1, a member of the GINS complex. We found that, after anti‐cancer drug administration, surviving GFP‐positive leukemia cells in the bone marrow were located adjacent to blood vessels, as previously reported in a subcutaneous solid tumor transplantation model. Treating THP‐1 and MEG‐1 cells with anti‐cancer drugs in vitro revealed that those most strongly expressing PSF1 were most chemoresistant, suggesting that PSF1 induces not only cell cycle progression but also facilitates cell survival. Indeed, when PSF1 expression was suppressed by shRNA, the growth rate was reduced and cell death was enhanced in both cell lines. Furthermore, PSF1 knockdown in leukemia cells led to a change in their location at a distance from the blood vessels in a bone marrow transplantation model. These findings potentially reflect a mechanism of escape of leukemic cells from chemotherapy and suggest that PSF1 may be a possible therapeutic target to enhance the effect of chemotherapy.

Identification of GINS1 as a therapeutic target in the cancer patients infected with COVID-19: a bioinformatics and system biology approach

“…GINS1 was required for cell proliferation in lung and colon carcinoma, and the inhibition of GINS1 suppressed the cell proliferation [ 64 , 65 ]. In cell cycle regulation, GINS1-knockdown caused cell cycle arrest at the quiescent G0/G1 phase in acute myelocytic leukemia and chronic myelocytic leukemia cells [ 23 ]. During the DNA replication, the GINS complex was recruited to form a complex, CDC45-MCM-GINS (CMG), triggering the elongation of replication [ 21 , 66 ].…”

“…The N-terminal domain forms an arch shape, and the C-terminal domain is on top of the arch [ 22 ]. In recent studies, GINS1 was reported to involve various processes of tumor genesis and development [ 23 , 24 ]. It has been demonstrated that GINS1 was highly expressed in various cancers, including intrahepatic cholangiocarcinoma, breast carcinoma, lung cancer, and colorectal cancer [ 24 , 25 ].…”

GINS Complex Subunit 2 Facilitates Gastric Adenocarcinoma Proliferation and Indicates Poor Prognosis

“…The involvement of GINS subunits in malignancies has been reported in recent studies. For example, high expression of GINS1 promotes drug resistance in leukemia cells (Hsieh et al 2020) and help predicts clinical outcomes of colorectal cancer patients (Bu et al 2020b). On the other hand, high GINS4 results in tumorigenesis of human bladder cancer, colorectal cancer, and hepatocellular carcinoma (Yamane et al 2016;Rong et al 2020;Zhang et al 2021).…”

Progress of Psf1 and prospects in the tumor: A review

“…These findings may reflect the mechanism of leukemia cells escaping from chemotherapy and suggest that Psf1 may be a therapeutic target to enhance the effect of chemotherapy. [34]…”