Drug-induced senescence bystander proliferation in prostate cancer cells in vitro and in vivo

Ewald, Jonathan A.; Desotelle, Joshua A.; Almassi, Nima; Jarrard, David F.

doi:10.1038/sj.bjc.6604288

Cited by 42 publications

(40 citation statements)

References 23 publications

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“…In these cells, the non-proliferative effect of mifepristone remained as long as 9 days following treatment removal, suggesting an irreversible growth arrest. Previous research has shown the propensity of LNCaP cells to enter irreversible growth arrest and senescence in response, for instance, to treatment with doxorubicin or to culture in androgen-free media [29,40]. We confirmed that LNCaP cells exposed to mifepristone become senescent upon removal of the drug as indicated by the increase in the activity of perinuclear SA-β-galactosidase.…”

Section: Discussionsupporting

confidence: 82%

Cytostasis and morphological changes induced by mifepristone in human metastatic cancer cells involve cytoskeletal filamentous actin reorganization and impairment of cell adhesion dynamics

et al. 2013

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BackgroundChanges in cell shape and plasticity in cytoskeletal dynamics are critically involved in cell adhesion, migration, invasion and the overall process of metastasis. Previous work in our laboratory demonstrated that the synthetic steroid mifepristone inhibited the growth of highly metastatic cancer cells, while simultaneously causing striking changes in cellular morphology. Here we assessed whether such morphological alterations developed in response to cytostatic concentrations of mifepristone are reversible or permanent, involve rearrangement of cytoskeletal proteins, and/or affect the adhesive capacity of the cells.MethodsCancer cell lines of the ovary (SKOV-3), breast (MDA-MB-231), prostate (LNCaP), and nervous system (U87MG) were exposed to cytostatic concentrations of mifepristone and studied by phase-contrast microscopy. The transient or permanent nature of the cytostasis and morphological changes caused by mifepristone was assessed, as well as the rearrangement of cytoskeletal proteins. De-adhesion and adhesion assays were utilized to determine if mifepristone-arrested and morphologically dysregulated cells had abnormal de-adhesion/adhesion dynamics when compared to vehicle-treated controls.ResultsMifepristone-treated cells displayed a long, thin, spindle-like shape with boundaries resembling those of loosely adhered cells. Growth arrest and morphology changes caused by mifepristone were reversible in SKOV-3, MDA-MB-231 and U87MG, but not in LNCaP cells that instead became senescent. All cancer cell types exposed to mifepristone displayed greatly increased actin ruffling in association with accelerated de-adhesion from the culture plate, and delayed adhesion capacity to various extracellular matrix components.ConclusionsCytostatic concentrations of mifepristone induced alterations in the cellular structure of a panel of aggressive, highly metastatic cancer cells of different tissues of origin. Such changes were associated with re-distribution of actin fibers that mainly form non-adhesive membrane ruffles, leading to dysregulated cellular adhesion capacity.

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Section: Discussionsupporting

confidence: 82%

Cytostasis and morphological changes induced by mifepristone in human metastatic cancer cells involve cytoskeletal filamentous actin reorganization and impairment of cell adhesion dynamics

et al. 2013

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“…TCS has been demonstrated in a variety of in vitro and in vivo models, as well as in human tumor samples 5. An emerging body of evidence has also confirmed that “irreversible” senescence can be overcome following chemotherapy and radiation 47, 48. These findings suggest that TCS during cancer treatment is likely to be associated with inevitable reproliferation of once dormant cancer cells and residual viable tissue after the surgery.…”

Section: Discussionmentioning

confidence: 83%

Polyploidy road to therapy‐induced cellular senescence and escape

Wang

Dong

et al. 2012

Intl Journal of Cancer

108

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Therapy-induced cellular senescence (TCS), characterized by prolonged cell cycle arrest, is an in vivo response of human cancers to chemotherapy and radiation. Unfortunately, TCS is reversible for a subset of senescent cells, leading to cellular reproliferation and ultimately tumor progression. This invariable consequence of TCS recapitulates the clinical treatment experience of patients with advanced cancer. We report the findings of a clinicopathological study in patients with locally advanced non-small cell lung cancer demonstrating that marker of in vivo TCS following neoadjuvant therapy prognosticate adverse clinical outcome. In our efforts to elucidate key molecular pathways underlying TCS and cell cycle escape, we have previously shown that the deregulation of mitotic kinase Cdk1 and its downstream effectors are important mediators of survival and cell cycle reentry. We now report that aberrant expression of Cdk1 interferes with apoptosis and promotes the formation of polyploid senescent cells during TCS. These polyploid senescent cells represent important transition states through which escape preferentially occurs. The Cdk1 pathway is in part modulated differentially by p21 and p27 two members of the KIP cyclin-dependent kinase inhibitor family during TCS. Altogether, these studies underscore the importance of TCS in cancer therapeutics.The primary objective of anticancer therapy is the eradication of cancer cells by inducing cell death via apoptosis, autophagy and mitotic catastrophe. Complete eradication of most solid tumors such as non-small cell lung cancer (NSCLC) is rarely achieved using conventional treatment because of various biological and physiological limitations. These factors include the high frequency of p53 mutations, aberrant expression of antiapoptotic proteins such as Bcl-2 and survivin and various resistance mechanisms which impair tumor responses to cancer treatment. 1-3 Additionally, normal organ tolerance, drug bioavailability and tissue penetration further limit the efficacy of conventional chemotherapy and radiation in clinical settings.Telomere-independent therapy-induced cellular senescence (TCS), also known as stressed-induced premature senescence and accelerated cellular senescence, is increasingly recognized to be an important concept in cancer biology. The characteristic prolonged state of cell cycle arrest which defines senescence is elicited by sublethal doses of chemotherapy and ionizing radiation. 4,5 Over the past decade, TCS has been clearly demonstrated in a variety of cancer tissue culture models following abbreviated courses of antineoplastic drugs at subtumoricidal concentrations. 6 These studies consistently show that senescence response can be invoked by a wide spectrum of agents, which suggests that shared downstream pathways may be triggered by various cellular damage and stress signals. A particularly surprising finding is that despite expected dependency on key players of the cell damage and replicative

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“…Later on, however, it was shown that although senescent human prostate cancer cells increased proliferation of co-cultured tumor cells in vitro, such accelerating impact on xenograft tumor cell growth in nude mice was not observed [8] indicating impact of some still unidentified factors on this phenomenon.…”

Section: Introductionmentioning

confidence: 99%

Tumor growth accelerated by chemotherapy-induced senescent cells is suppressed by treatment with IL-12 producing cellular vaccines

et al. 2016

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Standard-of-care chemo- or radio-therapy can induce, besides tumor cell death, also tumor cell senescence. While senescence is considered to be a principal barrier against tumorigenesis, senescent cells can survive in the organism for protracted periods of time and they can promote tumor development. Based on this emerging concept, we hypothesized that elimination of such potentially cancer-promoting senescent cells could offer a therapeutic benefit. To assess this possibility, here we first show that tumor growth of proliferating mouse TC-1 HPV-16-associated cancer cells in syngeneic mice becomes accelerated by co-administration of TC-1 or TRAMP-C2 prostate cancer cells made senescent by pre-treatment with the anti-cancer drug docetaxel, or lethally irradiated. Phenotypic analyses of tumor-explanted cells indicated that the observed acceleration of tumor growth was attributable to a protumorigenic environment created by the co-injected senescent and proliferating cancer cells rather than to escape of the docetaxel-treated cells from senescence. Notably, accelerated tumor growth was effectively inhibited by cell immunotherapy using irradiated TC-1 cells engineered to produce interleukin IL-12. Collectively, our data document that immunotherapy, such as the IL-12 treatment, can provide an effective strategy for elimination of the detrimental effects caused by bystander senescent tumor cells in vivo.

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Drug-induced senescence bystander proliferation in prostate cancer cells in vitro and in vivo

Cited by 42 publications

References 23 publications

Cytostasis and morphological changes induced by mifepristone in human metastatic cancer cells involve cytoskeletal filamentous actin reorganization and impairment of cell adhesion dynamics

Cytostasis and morphological changes induced by mifepristone in human metastatic cancer cells involve cytoskeletal filamentous actin reorganization and impairment of cell adhesion dynamics

Polyploidy road to therapy‐induced cellular senescence and escape

Tumor growth accelerated by chemotherapy-induced senescent cells is suppressed by treatment with IL-12 producing cellular vaccines

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