Downregulation of Pim-2 induces cell cycle arrest in the G0/G1 phase via the p53-non-dependent p21 signaling pathway

Abstract

Pim-2 is a serine/threonine protein kinase that is highly expressed in various types of cancer, with essential roles in the regulation of signal transduction cascades, which promote cell survival and proliferation. The present study demonstrated that Pim-2 was expressed in cells lines derived from hematopoietic tumors and lung cancer. In vitro, downregulation of Pim-2 by short interfering RNA inhibited proliferation and delayed G0/G1 cell cycle progression in K562 leukemia, RPMI-8226 multiple myeloma, and H1299 and A549 non-small cell lung carcinoma cell lines. Furthermore, downregulation of Pim-2 resulted in upregulation of cyclin-dependent kinase (CDK) inhibitor p21, irrespective of the p53 status. In addition, the present study revealed that CDK2 and phosphorylated retinoblastoma (pRb) were significantly downregulated. This finding suggested that inhibition of CDK2 and pRb expression via upregulated p21 was involved in the downregulation of Pim-2-induced G0/G1 cell cycle arrest in lung cancer and hematopoietic malignancy cells. These results suggested that Pim-2 may serve a role in hematopoietic tumors, lung cancer proliferation and cell cycle progression by regulating the p21 signaling pathway. Downregulation of Pim-2 decreased cancer cell proliferation. Therefore, Pim-2 may be a potential therapy target in clinical cancer therapy.

Inhibition of PIM2 in liver cancer decreases tumor cell proliferation in�vitro and in�vivo primarily through the modulation of cell cycle progression

“…One explanation we considered relies on the differential expression of the cell cycle inhibitor, p21 WAF1/CIP1 , which is dependent on the p53 status of the cells and seems to make HepG2 cells with wt p53 and thus higher p21 WAF1/CIP1 expression more sensitive to PIM2 knockdown than Huh-7 with mutant p53 and a low p21 WAF1/CIP1 expression. This is in line with the findings of Liu et al, who described a p21 WAF1/CIP1 -dependent cell cycle block in G0/G1 upon PIM2 knockdown in the non-small cell lung cancer cell lines A549 and H1299 (34). However, our findings in the Huh-7 cells also suggest an additional, p21 WAF1/CIP1 -independent mechanism of the cell cycle regulation by PIM2 in liver cancer cells, since the ectopic overexpression of wt p21 WAF1/CIP1 in this cell line led to an only slight increase in sensitivity towards PIM2 knockdown.…”

“…S4A). Recently, Liu et al reported that PIM2 induced cell cycle arrest in the G0/G1 phase via p53-independent, but p21 WAF1/CIP1 -dependent signaling in lung cancer cell lines (34). Thus, in this study, we examined whether the restoration of p21 WAF1/CIP1 expression in the Huh-7 cells would enable a more sensitive cell cycle regulation following PIM2 knockdown.…”

Reduced pim‑1 expression increases chemotherapeutic drug sensitivity in human androgen‑independent prostate cancer cells by inducing apoptosis

“…Three members of proto-oncogene serine/threonine kinase family have been identified, including pim-1, pim-2 and pim-3 (25,26). It has been reported that pim-1 is involved in regulating cell cycle progression and apoptosis (26); and has been detected to be heavily expressed in numerous cancers including prostate cancer, Burkitt's lymphoma, oral cancer and a variety of hematopoietic lymphomas (27,28). Therefore, to study the role of pim-1 in the prostate cancer physiology, endogenous pim-1 expression was knocked down in androgen-independent prostate cancer cells, including PC3, DU145 and PC3/DDP, using the shRNA approach.…”

Antifibrotic Agent Pirfenidone Suppresses Proliferation of Human Pancreatic Cancer Cells by Inducing G0/G1 Cell Cycle Arrest

“…Therefore, our results showed that PFD upregulated p21 levels without requiring functional p53 in PCCs. The several previous studies revealed that p53-independent mechanism for p21 upregulation may contribute to the cell cycle response [33][34][35]. Further studies are required to verify the existence of a p53-independent signaling pathway in this context.…”