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Cancers, Vol. 12, Pages 3260: Improving Radiation Response in Glioblastoma Using ECO/siRNA Nanoparticles Targeting DNA Damage Repair
Camphausen Radiation therapy is a mainstay in the standard of care for glioblastoma (GBM), thus inhibiting the DNA damage response (DDR) is a major strategy to improve radiation response and therapeutic outcomes. Small interfering RNA (siRNA) therapy holds immeasurable potential for the treatment of GBM, however delivery of the siRNA payload remains the largest obstacle for clinical implementation. Here we demonstrate the effectiveness of the novel nanomaterial, ECO (1-aminoethylimino[bis(N-oleoylcysteinylaminoethyl) propionamide]), to deliver siRNA targeting DDR proteins ataxia telangiectasia mutated and DNA-dependen...
Source: Cancers - November 4, 2020 Category: Cancer & Oncology Authors: Jennifer A. Lee Nadia Ayat Zhanhu Sun Philip J. Tofilon Zheng-Rong Lu Kevin Camphausen Tags: Article Source Type: research

Silencing of ATM expression by siRNA technique contributes to glioma stem cell radiosensitivity in vitro and in vivo.
In conclusion, silencing of ATM via the siRNA technique improved radiosensitivity of GSCs both in vitro and in vivo. PMID: 28560406 [PubMed - as supplied by publisher]
Source: Oncology Reports - June 2, 2017 Category: Cancer & Oncology Tags: Oncol Rep Source Type: research

Abstract B21: The selective ATR inhibitor VX-970 enhances the therapeutic effects of standards of care in glioblastoma
Glioblastoma (GBM) represents one of the most aggressive cancer types with the vast majority of patients succumbing to disease within the first five years. This dire prognosis reflects the limited efficacy of our frontline therapies which include radiation therapy and temozolomide (TMZ) chemotherapy. The cellular response to these therapies is critically mediated by DNA damage response signaling networks that are regulated by Ataxia Telangiectasia Mutated (ATM) and Ataxia Telangiectasia And Rad3-Related Protein (ATR). Preliminary studies from our laboratory suggest the ATR inhibitor VX-970 has single agent efficacy in both...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Burgenske, D., Mladek, A., Sarkaria, J. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B42: Silencing of DNA repair proteins with ECO/siRNA nanoparticles for the enhancement of radiation response in glioblastoma
In this study we investigate the use of these nanoparticles to deliver siRNA to inhibit ATM and DNApk activity and enhance radiation response in both glioma and glioma stem cell lines.Established glioma (U251) and glioma stem cell (NSC11) lines were used to evaluate the effectiveness of ECO nanoparticle delivery of siRNA in vitro . Cellular uptake of ECO nanoparticles loaded with fluorescent siRNA was assessed using flow cytometry and fluorescent microscopy, demonstrating the rapid uptake of ECO/siRNA nanoparticles in comparison to commercially available transfection agents. Protein and mRNA analyses revealed the kinetics ...
Source: Cancer Research - January 15, 2017 Category: Cancer & Oncology Authors: Jennifer A. Lee, Nadia Ayat, Anita Tandle, Zheng-Rong Lu, Kevin Camphausen Tags: Drug Delivery and Nanomedicine Source Type: research

Low-dose irradiation promotes proliferation of the human breast cancer MDA-MB-231 cells through accumulation of mutant P53.
Abstract Low-dose irradiation (LDIR) has been proven to have differential biological effects on normal mammalian somatic cells and cancer cells. Our previous study showed that p53 gene status is a critical factor regulating the effect of LDIR on cancer cells. We investigated the effect of LDIR on the breast cancer cell line MDA-MB-231 that harbors a mutant p53 gene, and the normal breast fibroblast cell line Hs 578Bst. In the present study, we showed that 150 mGy LDIR pormoted growth of MDA-MB-231 cells but not Hs 578Bst cells. Through cell cycle analyses, we found that LDIR accelerated cell cycle into S phase i...
Source: International Journal of Oncology - December 5, 2016 Category: Cancer & Oncology Authors: Li SJ, Liang XY, Li HJ, Li W, Zhou L, Chen HQ, Ye SG, Yu DH, Cui JW Tags: Int J Oncol Source Type: research

IGF-1R inhibition sensitizes breast cancer cells to ATM-Related Kinase (ATR) inhibitor and cisplatin.
Authors: O'Flanagan CH, O'Shea S, Lyons A, Fogarty FM, McCabe N, Kennedy RD, O'Connor R Abstract The complexity of the IGF-1 signalling axis is clearly a roadblock in targeting this receptor in cancer therapy. Here, we sought to identify mediators of resistance, and potential co-targets for IGF-1R inhibition. By using an siRNA functional screen with the IGF-1R tyrosine kinase inhibitor (TKI) BMS-754807 in MCF-7 cells we identified several genes encoding components of the DNA damage response (DDR) pathways as mediators of resistance to IGF-1R kinase inhibition. These included ATM and Ataxia Telangiectasia and RAD3-r...
Source: Oncotarget - July 30, 2016 Category: Cancer & Oncology Tags: Oncotarget Source Type: research

Silencing of ataxia-telangiectasia mutated by siRNA enhances the in vitro and in vivo radiosensitivity of glioma.
In conclusion, silencing of ATM via the siRNA technique could improve the in vitro and in vivo radiosensitivity of glioma cells. PMID: 27108486 [PubMed - as supplied by publisher]
Source: Oncology Reports - April 27, 2016 Category: Cancer & Oncology Tags: Oncol Rep Source Type: research

Abstract B29: LRP16 is an essential mediator for DNA double-strand breaks induced NF-kappaB activation
In this study, we demonstrate that LRP16 constitutively interacts with PARP1 and IKKgamma. This interaction is essential for efficient interactions among PARP1, IKKgamma, and PIASy, the modifications of IKKgamma, and the activation of NF-kappaB following DSB induction. The regulation of LRP16 in NF-kappaB activation is dependent on its poly (ADP-ribose) binding capability through the unique macro domain. The depletion of the DSB-specific sensor Ku80 resulted in a significant reduction in the physical interactions among LRP16, PARP1 and IKKgamma. Additionally, the knockdown of either endogenous Ku80 or Ku70 by siRNA markedl...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Wu, Z., Wang, C., Bai, M., Li, X., Mei, Q., Li, X., Wang, Y., Fu, X., Luo, G., Han, W. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Abstract 5193: Ataxia telangiectasia mutated relates to epithelial-mesenchymal transition in colorectal cancer
Conclusions: ATM might be a critical regulator of EMT in colorectal cancer invasion.Citation Format: Hidena Takahashi, Masashi Tsuruta, Hirotoshi Hasegawa, Koji Okabayashi, Ryo Seishima, Shimpei Matsui, Toru Yamada, Takayuki Kondo, Takehiro Shimada, Mutsuhito Matsuda, Masashi Yahagi, Yusuke Yoshikawa, Yusuke Asada, Kiyoaki Sugiura, Yoshiyuki Suzuki, Yuki Tajima, Junpei Nakadai, Yuko Kitagawa. Ataxia telangiectasia mutated relates to epithelial-mesenchymal transition in colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Takahashi, H., Tsuruta, M., Hasegawa, H., Okabayashi, K., Seishima, R., Matsui, S., Yamada, T., Kondo, T., Shimada, T., Matsuda, M., Yahagi, M., Yoshikawa, Y., Asada, Y., Sugiura, K., Suzuki, Y., Tajima, Y., Nakadai, J., Kitagawa, Y. Tags: Tumor Biology Source Type: research

PTEN-Deficient Tumor Cells Are Dependent on ATM Signaling
In this study, we took an siRNA screening strategy to identify other tumor suppressors that, when inhibited, similarly sensitized cells to ATM inhibition. In this manner, we determined that PTEN and ATM were synthetically lethal when jointly inhibited. PTEN-deficient cells exhibited elevated levels of reactive oxygen species, increased endogenous DNA damage, and constitutive ATM activation. ATM inhibition caused catastrophic DNA damage, mitotic cell cycle arrest, and apoptosis specifically in PTEN-deficient cells in comparison with wild-type cells. Antioxidants abrogated the increase in DNA damage and ATM activation in PTE...
Source: Cancer Research - May 31, 2015 Category: Cancer & Oncology Authors: McCabe, N., Hanna, C., Walker, S. M., Gonda, D., Li, J., Wikstrom, K., Savage, K. I., Butterworth, K. T., Chen, C., Harkin, D. P., Prise, K. M., Kennedy, R. D. Tags: Priority Reports Source Type: research

RNF8 plays an important role in the radioresistance of human nasopharyngeal cancer cells in vitro.
Authors: Wang M, Chen X, Chen H, Zhang X, Li J, Gong H, Shiyan C, Yang F Abstract Tumor residue or recurrence is common after radiation therapy for nasopharyngeal cancer (NPC) since the tumor cells can repair irradiation-induced DNA damage. The ubiquitination cascade mediates the assembly of repair and signaling proteins at sites of DNA double-strand breaks (DSBs). Ring finger protein 8 (RNF8) is an E3 ubiquitin ligase that triggers ubiquitination at the site of DSBs. The present study aimed to identify whether and how RNF8 small interfering RNA (siRNA) treatment enhances the radiosensitivity of irradiated human ...
Source: Oncology Reports - May 9, 2015 Category: Cancer & Oncology Tags: Oncol Rep Source Type: research

Resveratrol analogue (E)-8-acetoxy-2-2-(3,4-diacetoxyphenyl)ethenyl-quinazoline induces G2/M cell cycle arrest through the activation of ATM/ATR in human cervical carcinoma HeLa cells.
Authors: Kim JY, Choi HE, Lee HH, Shin JS, Shin DH, Choi JH, Lee YS, Lee KT Abstract Styrylquinazolines are synthetic analogues of resveratrol and have been suggested to cause anti-inflammatory activity by modulating prostaglandin E2 (PGE2) production. In the present study, we evaluated cytotoxic effects of various styrylquinazoline derivatives and found that (E)-8-acetoxy-2-[2-(3,4-diacetoxyphenyl)ethenyl]-quinazoline (8-ADEQ) most potently inhibited the proliferation of the human cervical carcinoma HeLa cells. Exploring the growth-inhibitory mechanisms of 8-ADEQ, we found that it causes a cell cycle arrest at the...
Source: Oncology Reports - April 1, 2015 Category: Cancer & Oncology Tags: Oncol Rep Source Type: research

ATR and ATM Loss-of-Function
Mechanisms to maintain genomic integrity are essential for cells to remain viable. Not surprisingly, disruption of key DNA damage response pathway factors, such as ataxia telangiectasia-mutated (ATM)/ataxia telangiectasia and RAD3-related (ATR) results in loss of genomic integrity. Here, a synthetic lethal siRNA-screening approach not only confirmed ATM but identified additional replication checkpoint proteins, when ablated, enhanced ATR inhibitor (ATRi) response in a high-content -H2AX assay. Cancers with inactivating ATM mutations exhibit impaired DNA double-stranded break (DSB) repair and rely on compensatory repair pat...
Source: Molecular Cancer Research - January 15, 2015 Category: Cancer & Oncology Authors: Menezes, D. L., Holt, J., Tang, Y., Feng, J., Barsanti, P., Pan, Y., Ghoddusi, M., Zhang, W., Thomas, G., Holash, J., Lees, E., Taricani, L. Tags: DNA Damage and Repair Source Type: research

An ATM-MPG Axis Promotes Resistance to Alkylating Agents Research Articles
This article is highlighted in the In This Issue feature, p. 1103
Source: Cancer Discovery - September 30, 2014 Category: Cancer & Oncology Authors: Agnihotri, S., Burrell, K., Buczkowicz, P., Remke, M., Golbourn, B., Chornenkyy, Y., Gajadhar, A., Fernandez, N. A., Clarke, I. D., Barszczyk, M. S., Pajovic, S., Ternamian, C., Head, R., Sabha, N., Sobol, R. W., Taylor, M. D., Rutka, J. T., Jones, C., Di Tags: Preclinical Intervention, Preclinical Intervention: In Vitro: Drugs, Mechanisms Research Articles Source Type: research

A hormone-dependent feedback-loop controls androgen receptor levels by limiting MID1, a novel translation enhancer and promoter of oncogenic signaling
Conclusion: Promotion of AR, in addition to enhancement of the Akt-, NFkappaB-, and Hh-pathways by sustained MID1-upregulation during androgen deprivation therapy provides a powerful proliferative scenario for PCa progression into castration resistance. Thus MID1 represents a novel, multi-faceted player in PCa and a promising target to treat castration resistant prostate cancer.
Source: Molecular Cancer - June 9, 2014 Category: Cancer & Oncology Authors: Andrea KöhlerÜmmühan DemirEva KicksteinSybille KraussJohanna AignerBeatriz Aranda-OrgillésAntonios KaragiannidisClemens AchmüllerHuajie BuAndrea WunderlichMichal-Ruth SchweigerGeorg SchaeferSusann SchweigerHelmut KlockerRainer Schneider Source Type: research

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