Molecular Pathways: Harnessing E2F1 Regulation for Prosenescence Therapy in p53-Defective Cancer Cells

Abstract

Induction of terminal proliferation arrest, senescence, is important for in vivo tumor-suppressive function of p53. Moreover, p53-mutant cells are highly resistant to senescence induction by either oncogenic signaling during cellular transformation or in response to different therapies. Senescence resistance in p53-mutant cells has been attributed mostly to inhibition of the checkpoint function of p53 in response to senescence-inducing stress signals. Here, we review very recent evidence that offers an alternative explanation for senescence resistance in p53-defective cancer cells: p21-mediated E2F1 expression. We discuss the potential relevance of these findings for senescence-inducing therapies and highlight cyclin-dependent kinases (CDK) and mechanisms downstream of retinoblastoma protein (RB) as prospective prosenescence therapeutic targets. In particular, we discuss recent findings indicating an important role for the E2F1-CIP2A feedback loop in causing senescence resistance in p53-compromised cancer cells. We further propose that targeting of the E2F1-CIP2A feedback loop could provide a prosenescence therapeutic approach that is effective in both p53-deficient and RB-deficient cancer cells, which together constitute the great majority of all cancer cells. Diagnostic evaluation of the described senescence resistance mechanisms in human tumors might also be informative for patient stratification for already existing therapies. Clin Cancer Res; 20(14); 3644-50. Ó2014 AACR.

The HDM2 (MDM2) Inhibitor NVP-CGM097 Inhibits Tumor Cell Proliferation and Shows Additive Effects with 5-Fluorouracil on the p53-p21-Rb-E2F1 Cascade in the p53^{wild type} Neuroendocrine Tumor Cell Line GOT1

“…2 ). These findings coincide with known effects of other MDM2 inhibitors on the p53/MDM2/ PUMA/p21/pRb/E2F1 cascade [12,45,46] . Further p53-mediated downstream effects alter the p53/MDM2/ PUMA/p21/pRb/E2F1 cascade and mediate the antitumoral effects of MDM2 inhibitors [12,35,46] .…”

“…These findings indicate that NVP-CGM097 is a highly specific MDM2 inhibitor increasing p53, PUMA, and p21 expression and interacting with the MDM2/p53/PUMA/p21/Rb/E2F1 cascade [46] . CDK4/6-cyclin D-or CDK2-cyclin E-mediated phosphorylation of Rb protein results in its inactivation, dissociation of the pRb/E2F complex, and repression of E2F transcription factors [46,80] . Double knockout experiments in Men1+/-Cdk4-/-mice indicate that CDK4 is essential for NET development [81] .…”

DNA damage and S phase-dependent E2F1 stabilization requires the cIAP1 E3-ubiquitin ligase and is associated with K63-poly-ubiquitination on lysine 161/164 residues

“…Its protein expression level is increased in many human cancers such as hepatocarcinomas, digestive adenocarcinomas and ovarian cancers, and its downregulation in p53- and RB-compromised cancer cells can trigger their senescence. 1 Further understanding of E2F1 expression regulation would help to develop strategies targeting this protein in cancer cells.…”

E2F1‐Ror2 signaling mediates coordinated transcriptional regulation to promote G1/S phase transition in bFGF‐stimulated NIH/3T3 fibroblasts

“…Furthermore, Ror2 is expressed highly in embryonic tissues that contain abundantly proliferating cells, indicating that E2F1‐induced transcriptional activation of Ror2 might also be involved in the expression of Ror2 in these proliferating cells during embryogenesis. E2F1 is also activated strongly in cancer cells through various mechanisms, including activation of oncogenes and inhibition of tumor suppressor genes . It has been shown that Ror2 is expressed highly in lung adenocarcinoma cells harboring p53 loss‐of‐function mutations and in human papillomavirus (HPV)‐positive head and neck squamous cell carcinoma, where HPV oncogenic protein E7 represses Rb .…”