The Cell Cycle Inhibitors p21 Cip1 and p27 Kip1 Control Proliferation but Enhance DNA Damage Resistance of Glioma Stem Cells

Abstract

High-grade gliomas are the most prevalent and lethal primary brain tumors. They display a hierarchical arrangement with a population of self-renewing and highly tumorigenic cells called cancer stem cells. These cells are thought to be responsible for tumor recurrence, which make them main candidates for targeted therapies. Unbridled cell cycle progression may explain the selective sensitivity of some cancer cells to treatments. The members of the Cip/Kip family p21Cip1 and p27Kip1 were initially considered as tumor suppressors based on their ability to block proliferation. However, they are currently looked at as proteins with dual roles in cancer: one as tumor suppressor and the other as oncogene. Therefore, the aim of this study was to determine the functions of these cell cycle inhibitors in five patient-derived glioma stem cell–enriched cell lines. We found that these proteins are functional in glioma stem cells. They negatively regulate cell cycle progression both in unstressed conditions and in response to genotoxic stress. In addition, p27Kip1 is upregulated in nutrient-restricted and differentiating cells, suggesting that this Cip/Kip is a mediator of antimitogenic signals in glioma cells. Importantly, the lack of these proteins impairs cell cycle halt in response to genotoxic agents, rendering cells more vulnerable to DNA damage. For these reasons, these proteins may operate both as tumor suppressors, limiting cell proliferation, and as oncogenes, conferring cell resistance to DNA damage. Thus, deepening our knowledge on the biological functions of these Cip/Kips may shed light on how some cancer cells develop drug resistance.

LncRNA LINC00963 Promotes Tumorigenesis and Radioresistance in Breast Cancer by Sponging miR-324-3p and Inducing ACK1 Expression

“…It is well known that p27 acts as a cell cycle repressor 17 . Induction of p27 can impair cell cycle progression and render cells more susceptible to DNA damage 18 . Therefore, the growth-suppressive activity of LINC00963 is causally linked to alteration of cell-cycle regulatory proteins.…”

The Multifaceted p21 (Cip1/Waf1/CDKN1A) in Cell Differentiation, Migration and Cancer Therapy

“…p21 is indispensable for maintaining self-renewal of leukemia stem cells [88], and it is able to inhibit oncogene-induced EMT and breast tumor stem cells in transgenic mice [101]. In a study with five patient-derived glioma stem cell-enriched cell lines, the authors have reported that p21 and p27 operate both as tumor suppressors, limiting cell proliferation, but also as oncogenes, conferring cell resistance to DNA damage and developing drug resistance [189]. Further investigations are mandatory to delineate if suppression of p21 serves as a therapeutic target, though its antisense therapy radiosensitizes human colon cancer cells [190] and glioma cells [191] to apoptosis.…”

HOTAIR‐EZH2 inhibitor AC1Q3QWB upregulates CWF19L1 and enhances cell cycle inhibition of CDK4/6 inhibitor palbociclib in glioma

“…Sinomenine promotes p53 expression and acetylation, leading to G0/G1 cell cycle arrest and apoptosis 4 . P21 acts as a tumor suppressor gene to stop the cell cycle and limit cell proliferation 5 . Furthermore, 40‐50% of gliomas have PTEN inactivation, leading to the abnormal activation of PI3K activity and downstream signaling pathways 6 .…”