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.
Highlights
Cellular senescence refers to a phenomenon in which cells are permanently growth-arrested due to the accumulation of extensive and unrecoverable damage to telomeric and/or non-telomericDNA
In vitro estimation of the replicative lifespan of primary epithelial ovarian cancer cells (pEOCs) established form ovarian tumors revealed that the growth capacity of these cells is limited and that they become growth-arrested after approximately five population doublings
Apart from the endogenous reactive oxygen species (ROS) induction, may be induced by extracellular stressors [43], we examined if the senescence phenotype in pEOCs, marked by the presence of SA-β-Gal and γ-H2A.X/53BP1 foci, may be elicited in a paracrine manner by proteins released to environment by normal peritoneal mesothelial cells or fibroblasts, or present in malignant ascites. pEOCs maintained under such conditions were sensitive to the pro-senescence impact of the normal cells, especially their senescent forms, and malignant ascites
Summary
Cellular senescence refers to a phenomenon in which cells are permanently growth-arrested due to the accumulation of extensive and unrecoverable damage to telomeric and/or non-telomericDNA. The development of senescence is associated with characteristic changes in gene expression, cell phenotype, and function [1]. The development of a senescence phenotype has been identified in tumors subjected to clinically relevant doses of radiation [2] and chemotherapy, including cisplatin, carboplatin, doxorubicin, and etoposide [3]. Very little is known about the spontaneous senescence of cancer cells as a therapy independent process. In breast cancer patients who had not received chemotherapy, 10% of tumors displayed senescence-associated β-galactosidase (SA-β-Gal) [4]. To therapy-induced senescence, the spontaneous senescence of cancer cells is often treated as an artifact and the mechanisms and potential clinical significance of this poorly characterized phenomenon remains unclear. It must be stressed that the senescence of normal cells has been considered a pro-cancerogenic phenomenon
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