Telomeric DNA induces apoptosis and senescence of human breast carcinoma cells

Yaar, Mina; Eller, Mark S.; Panova, Izabela P.; Kubera, John; Wee, Lee Hng; Cowan, Kenneth H.; Gilchrest, Barbara A.

doi:10.1186/bcr1646

Cited by 53 publications

(137 citation statements)

References 78 publications

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“…8,11,15,35 In the present study, T-oligo treatment increased SA-β-gal expression, induced a morphology similar to that of senescent cells, and decreased clonogenic capacity in melanoma cells, suggesting that T-oligo-induced senescence inhibited their growth in vitro. The TAp73 tumor suppressor isoform of p73 mediates apoptosis irrespective of p53 status.…”

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confidence: 85%

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Novel delivery system for T-oligo using a nanocomplex formed with an alpha helical peptide for melanoma therapy

Uppada¹,

Erickson²,

Wojdyla³

et al. 2013

IJN

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Oligonucleotides homologous to 3′-telomere overhang (T-oligos) trigger inherent telomere-based DNA damage responses mediated by p53 and/or ATM and induce senescence or apoptosis in various cancerous cells. However, T-oligo has limited stability in vivo due to serum and intracellular nucleases. To develop T-oligo as an innovative, effective therapeutic drug and to understand its mechanism of action, we investigated the antitumor effects of T-oligo or T-oligo complexed with a novel cationic alpha helical peptide, PVBLG-8 (PVBLG), in a p53 null melanoma cell line both in vitro and in vivo. The uptake of T-oligo by MM-AN cells was confirmed by immunofluorescence, and fluorescence-activated cell sorting analysis indicated that the T-oligo-PVBLG nanocomplex increased uptake by 15-fold. In vitro results showed a 3-fold increase in MM-AN cell growth inhibition by the T-oligo-PVBLG nanocomplex compared with T-oligo alone. Treatment of preformed tumors in immunodeficient mice with the T-oligo-PVBLG nanocomplex resulted in a 3-fold reduction in tumor volume compared with T-oligo alone. This reduction in tumor volume was associated with decreased vascular endothelial growth factor expression and induction of thrombospondin-1 expression and apoptosis. Moreover, T-oligo treatment downregulated procaspase-3 and procaspase-7 and increased catalytic activity of caspase-3 by 4-fold in MM-AN cells. Furthermore, T-oligo induced a 10-fold increase of senescence and upregulated the melanoma tumor-associated antigens MART-1, tyrosinase, and thrombospondin-1 in MM-AN cells, which are currently being targeted for melanoma immunotherapy. Interestingly, siRNA-mediated knockdown of p73 (4–10-fold) abolished this upregulation of tumor-associated antigens. In summary, we suggest a key role of p73 in mediating the anticancer effects of T-oligo and introduce a novel nanoparticle, the T-oligo-PVBLG nanocomplex, as an effective anticancer therapeutic.

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confidence: 85%

“…T-oligo mimics the exposure of the 3′ telomere overhang and induces DNA damage response (DDR) signals in several cancers. [8][9][10][11][12][13] T-oligo mediates DDRs by activating…”

Section: Introductionmentioning

confidence: 99%

Novel delivery system for T-oligo using a nanocomplex formed with an alpha helical peptide for melanoma therapy

Uppada¹,

Erickson²,

Wojdyla³

et al. 2013

IJN

View full text Add to dashboard Cite

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“…This decrease in telomere length can be considered as a sign of replicative senescence, eventually resulting in the secretion of SASP factors, which are thought to initiate parturition during normal labor (Behnia et al 2015). Moreover, telomere mimetics (TTAGGG (2) repeat sequences), which induce cellular senescence in multiple cancer cells (Klungland et al 1999, Yaar et al 2007, Sarkar & Faller 2011, Rankin et al 2012, Pitman et al 2013, Puri et al 2014, can also cause amnion cell oxidative stress, MAPK14 activation and cellular senescence in fetal membranes (Polettini et al 2015b). Telomere fragments also increased the expression of SASP factors IL6 and IL8 from amnion epithelial cells, suggesting a mechanism of sterile inflammation in the intrauterine cavity.…”

Section: :2mentioning

confidence: 99%

Positive and negative effects of cellular senescence during female reproductive aging and pregnancy

Velarde

Menon

2016

Journal of Endocrinology

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Cellular senescence is a phenomenon occurring when cells are no longer able to divide even after treatment with growth stimuli. Because senescent cells are typically associated with aging and age-related diseases, cellular senescence is hypothesized to contribute to the age-related decline in reproductive function. However, some data suggest that senescent cells may also be important for normal physiological functions during pregnancy. Herein, we review the positive and negative effects of cellular senescence on female reproductive aging and pregnancy. We discuss how senescent cells accelerate female reproductive aging by promoting the decline in the number of ovarian follicles and increasing complications during pregnancy. We also describe how cellular senescence plays an important role in placental and fetal development as a beneficial process, ensuring proper homeostasis during pregnancy.

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“…7,49 Our data show a significant decrease in Ki-67(ϩ) presumptively proliferative cells in pTT-versus vehicle-treated BCC nests, as well as an increase in the number of TUNEL(ϩ) cells, consistent with anti-proliferative and proapoptotic effects of T-oligos that we have previously reported for several malignant cell lines. 20,26,27,50 UV exposure induces Cox-2 expression in murine skin 49 and Cox-2 is known to be anti-apoptotic and proangiogenetic in BCCs and other tumors. 51 Oral administration of cyclooxygenase inhibitors (coxibs) reduces development of SCCs in hairless mice.…”

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confidence: 99%

“…24 -26 Moreover, both in vitro and in vivo, T-oligos lead to apoptosis and/or senescence of malignant cells, while inducing only protective responses in normal cells. 25,26 Complete telomere homologs have not been used for topical application because of anticipated poor percutaneous penetration. However, topical application of thymine dinucleotide (pTT), one third of the mammalian telomere repeat sequence TTAGGG, 20 reduces UV-induced mutations and photocarcinogenesis in hairless mice via p53 activation, transient cell cycle arrest, and increased DNA repair capacity.…”

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confidence: 99%

Topical Thymidine Dinucleotide Treatment Reduces Development of Ultraviolet-Induced Basal Cell Carcinoma in Ptch-1+/− Mice

Arad

Zattra

Hebert³

et al. 2008

The American Journal of Pathology

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Treatment with thymidine dinucleotide (pTT) has well documented DNA-protective effects and reduces development of squamous cell carcinoma in UV-irradiated mice. The preventive effect of pTT on basal cell carcinoma (BCC) was evaluated in UV-irradiated Ptch-1 ؉/؊ mice, a model of the human disease Gorlin syndrome. Topical pTT treatment significantly reduced the number and size (P < 0.001) of BCCs in murine skin after 7 months of chronic irradiation. Skin biopsies collected 24 hours after the final UV exposure showed that pTT reduced the number of nuclei positive for cyclobutane pyrimidine dimers by 40% (P < 0.0002) and for 8-hydroxy-2-deoxyguanosine by 61% (P < 0.01 compared with vehicle control). Immunostaining with an antibody specific for mutated p53 revealed 63% fewer positive patches in BCCs of pTTtreated mice compared with controls (P < 0.01), and the number of Ki-67-positive cells was decreased by 56% (P < 0.01) in pTT-treated tumor-free epidermis and by 76% (P < 0.001) in BCC tumor nests (P < 0.001). Terminal dUTP nick-end labeling staining revealed a 213% increase (P < 0.04) in the number of apoptotic cells in BCCs of pTT-treated mice. Cox-2 immunostaining was decreased by 80% in tumor-free epidermis of pTT-treated mice compared with controls (P < 0.01). We conclude that topical pTT treatment during a prolonged period of intermittent UV exposure decreases the number and size of UV-induced BCCs through several anti-cancer mechanisms. 1 Like squamous cell carcinomas (SCCs), BCCs are associated with fair skin and chronic sunlight exposure, 2,3 but the relationship is more complex and studies to date have failed to show that sun protection reduces development of BCCs, in contrast to SCCs.1 Moreover, BCCs and SCCs differ in their responsiveness to certain chemopreventive agents. For example, BCC development is inhibited strongly by topical retinoids but not by oral nonsteroidal anti-inflammatory drugs (NSAIDs) or green tea.4,5 By contrast, murine SCC photocarcinogenesis is inhibited poorly by topical retinoids and quite well by oral NSAIDs or green tea. 4,6 These differing effects of UV radiation and chemopreventive agents on BCC versus SCC, in combination with the large socioeconomic burden of BCCs, 7 stimulated us to test thymidine dinucleotide (pTT), an agent already demonstrated to prevent SCCs in UV-irradiated mice 8 for its ability to reduce BCC development.Studies during the past decade have tied BCC tumorigenesis quite firmly to activated hedgehog signaling, a Research involving processing tissue for evaluation of microscopic BCCs, routine histology, immunofluorostaining image, and statistical analyses, and manuscript preparation were performed at the

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Telomeric DNA induces apoptosis and senescence of human breast carcinoma cells

Cited by 53 publications

References 78 publications

Novel delivery system for T-oligo using a nanocomplex formed with an alpha helical peptide for melanoma therapy

Novel delivery system for T-oligo using a nanocomplex formed with an alpha helical peptide for melanoma therapy

Positive and negative effects of cellular senescence during female reproductive aging and pregnancy

Topical Thymidine Dinucleotide Treatment Reduces Development of Ultraviolet-Induced Basal Cell Carcinoma in Ptch-1+/− Mice

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