Deciphering the Molecular Mechanism of Spontaneous Senescence in Primary Epithelial Ovarian Cancer Cells

Abstract

Spontaneous senescence of cancer cells remains a puzzling and poorly understood phenomenon. Here we comprehensively characterize this process in primary epithelial ovarian cancer cells (pEOCs). Analysis of tumors from ovarian cancer patients showed an abundance of senescent cells in vivo. Further, serially passaged pEOCs become senescent after a few divisions. These senescent cultures display trace proliferation, high expression of senescence biomarkers (SA-β-Gal, γ-H2A.X), growth-arrest in the G1 phase, increased level of cyclins D1, D2, decreased cyclin B1, up-regulated p16, p21, and p53 proteins, eroded telomeres, reduced activity of telomerase, predominantly non-telomeric DNA damage, activated AKT, AP-1, and ERK1/2 signaling, diminished JNK, NF-κB, and STAT3 pathways, increased formation of reactive oxygen species, unchanged activity of antioxidants, increased oxidative damage to DNA and proteins, and dysfunctional mitochondria. Moreover, pEOC senescence is inducible by normal peritoneal mesothelium, fibroblasts, and malignant ascites via the paracrine activity of GRO-1, HGF, and TGF-β1. Collectively, pEOCs undergo spontaneous senescence in a mosaic, telomere-dependent and telomere-independent manner, plausibly in an oxidative stress-dependent mechanism. The process may also be activated by extracellular stimuli. The biological and clinical significance of pEOC senescence remains to be explored.

Molecular Biology of Ovarian Cancer: From Mechanisms of Intraperitoneal Metastasis to Therapeutic Opportunities

“…These studies portray the CD83 molecule as an essential regulator of OC progression, and a potential target for therapeutic interventions. The same conclusions may apply to the findings provided by Pakuła and co-workers, who described, as the first worldwide, that primary OC cells obtained from patients who had not received chemotherapy may undergo spontaneous, replicative senescence [ 11 ]. In this paper, the authors comprehensively describe the molecular mechanisms of OC cell senescence, and demonstrate that this process may be, at least partly, induced by normal peritoneal cells (mesothelium and fibroblasts), as well as by constituents of malignant ascites.…”

Patient-Specific Variables Determine the Extent of Cellular Senescence Biomarkers in Ovarian Tumors In Vivo

“…It is plausible that senescent cells whose fraction in aged people is higher [ 15 ] may also induce paracrine senescence in cancer cells in vivo. This hypothesis has support in the observations that senescent mesothelial cells lie in close proximity to ovarian cancer cells within a tumor [ 17 ] and that conditioned medium from these cells is capable of triggering the development of a senescence phenotype in primary epithelial ovarian cancer cells in vitro with GRO-1, HGF, and TGF-β1 as mediators [ 8 ]. The role of malignant ascites may be similar, as they were found to contain factors eliciting cellular senescence in normal cells [ 18 ].…”

“…Our group recently revealed that ovarian tumors obtained from chemotherapy-naïve patients contain a significant fraction of senescent cells. Potential triggers of this phenomenon and its molecular mechanisms have been further delineated using cell cultures established from those tumors [ 8 ]. At the same time, no attempts have been made to address the role of patient aging in the development of senescence of cancer cells in tumors in vivo.…”

Carboplatin-induced Senescence in Ovarian Cancer Cells Is Reversed Through EGFR and NF-κB Signaling

“…According to our study, ovarian cancer cells recovered from carboplatin-induced senescence became the major resource for metastases and recurrence [14,29,33] . Chemotherapeutic compounds targeting senescent cancer cells might be used develop a combination treatment for standard chemotherapy.…”