Preventing Damage Limitation: Targeting DNA-PKcs and DNA Double-Strand Break Repair Pathways for Ovarian Cancer Therapy

Dungl, Daniela A.; Maginn, Elaina N.; Stronach, Euan A.

doi:10.3389/fonc.2015.00240

Cited by 29 publications

(21 citation statements)

References 98 publications

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“…DSB can be repaired by HR or non-homologous end joining, resulting in cell survival. BRCA2 was the pivotal molecule in HR, and RDA51 was the downstream effector of BRCA2 (Dungl et al 2015, Katsuki & Takata 2016. The present data demonstrated that CDDP induced an increase in the RAD51 protein level in vitro and in vivo (i.e., the signal of DNA damages will initiate repair), which was suppressed in silencing BRCA2.…”

Section: :1supporting

confidence: 50%

Knockdown of BRCA2 enhances cisplatin and cisplatin-induced autophagy in ovarian cancer cells

Wan

Dai

Wang

et al. 2018

Endocrine-Related Cancer

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Clinical implications of the BRCA2 expression level on treatments of ovarian cancer are controversial. Here, we demonstrated that platinum-resistant cancer had a higher percentage of high BRCA2 level (87.5% vs 43.6%, = 0.001), and that patients with a low BRCA2 level in cancer tissues had longer progression-free survival (with a median time of 28.0 vs 12.0 months, < 0.001) and platinum-free duration (with a median time of 19.0 vs 5.0 months, < 0.001) compared with those with a high BRCA2 level. In human ovarian cancer cell lines CAOV-3 and ES-2, cisplatin induced an upregulation of the RAD51 protein, which was inhibited after silencing ; silencing enhanced the action of cisplatin and Knockdown of BRCA2 promoted cisplatin-induced autophagy. Interestingly, the autophagy blocker chloroquine enhanced cisplatin in BRCA2-silenced cells accompanied by an increase in apoptotic cells, which did not occur in BRCA2-intact cells; chloroquine enhanced the efficacy of cisplatin against BRCA2-silenced CAOV-3 tumors , with an increase in LC3-II level in tumor tissues. Sensitization of cisplatin was also observed in BRCA2-silenced CAOV-3 cells after inhibiting ATG7, confirming that chloroquine modulated the sensitivity via the autophagy pathway. These data suggest that a low BRCA2 level can predict better platinum sensitivity and prognosis, and that the modulation of autophagy can be a chemosensitizer for certain cancers.

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Section: :1supporting

confidence: 50%

Knockdown of BRCA2 enhances cisplatin and cisplatin-induced autophagy in ovarian cancer cells

Wan

Dai

Wang

et al. 2018

Endocrine-Related Cancer

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“…DNA-PKc is induced in response to doxorubicin and plays a key role in the repair of DSBs by non-homologous end-joining (NHEJ). Inhibition of DNA-PKcs has been considered as a novel and attractive approach to decrease resistance to therapeutically induced DSBs 35 – 37 , but data concerning its role in senescence are scarce. Rocourt et al showed that pretreatment of normal human diploid fibroblasts with DNA-PKcs kinase inhibitor NU 7026 suppressed selenium-induced senescence response 38 and Salminen et al discovered that this kinase was downregulated in senescent fibroblasts, which could probably contribute to accumulation of DNA damage during aging 39 .…”

Section: Discussionmentioning

confidence: 99%

Insight into the role of PIKK family members and NF-кB in DNAdamage-induced senescence and senescence-associated secretory phenotype of colon cancer cells

et al. 2018

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Senescence of cancer cells is an important outcome of treatment of many cancer types. Cell senescence is a permanent cell cycle arrest induced by stress conditions, including DNA damage. DNA damage activates DNA damage response (DDR), which involves members of the phosphatidylinositol 3-kinase-related kinase (PIKK) superfamily: protein kinases ATM, ATR, and DNA-PKcs. The so-far collected data indicate that ATM, with its downstream targets CHK2, p53, and p21, is the key protein involved in DDR-dependent senescence. It was also documented that the so-called senescence-associated secretory phenotype-SASP relies on ATM/CHK2, and not on p53 signaling. Moreover, genotoxic agents used in cancer treatment can activate NF-κB, which also induces transcription of SASP genes. In this paper, we have studied the involvement of three PIKK family members in colon cancer cell senescence and connection between DNA-damage-induced senescence and NF-κB-regulated SASP in p53-proficient and p53-deficient colon cancer cells treated with doxorubicin. We showed that doxorubicin induced cell senescence in both p53+/+ and p53−/− HCT116 cells, proving that this process is p53-independent. Senescence was successfully abrogated by a PIKK inhibitor, caffeine, or by simultaneous silencing of three PIKKs by specific siRNAs. By silencing individual members of PIKK family and analyzing common markers of senescence, the level of p21 and SA-β-Gal activity, we came to the conclusion that ATR kinase is crucial for the onset of senescence as, in contrast to ATM and DNA-PKsc, it could not be fully substituted by other PIKKs. Moreover, we showed that in case of silencing the three PIKKs, there was no SASP reduction accompanying the decrease in the level of p21 and SA-β-Gal (Senescence-Associated-β-Galactosidase) activity; whereas knocking down the NF-κB component, p65, abrogated SASP, but did not affect other markers of senescence, proving that DNA damage regulated senescence independently and NF-κB evoked SASP.

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“…Activated ATM triggers subsequent survival signals for regulation of cell cycle arrest, repair, apoptosis, and senescence 25 . One of these pro-survival signals is Akt (aka PKB), a key player of cell survival and DNA repair 26 , 27 . We determined whether (S)-crizotinib activated Akt in the SGC-7901 and BGC-823 cells by determining phosphorylation at Thr308 and Ser473.…”

Section: Resultsmentioning

confidence: 99%

(S)-crizotinib reduces gastric cancer growth through oxidative DNA damage and triggers pro-survival akt signal

Chen

Lian

et al. 2018

Cell Death Dis

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Gastric cancer (GC), a common gastrointestinal malignancy worldwide, has poor prognosis and frequent recurrence. There is a great need to identify effective therapy for GC. Crizotinib is a multi-targeted, clinically available oral tyrosine kinase inhibitor approved for lung cancer, but its use for the highly heterogeneous disease of GC is unknown. The goal of this study was to investigate the anti-cancer mechanisms of the (S)-crizotinib in inhibiting GC growth. Human GC cell lines (SGC-7901 and BGC-823) and the (S)-crizotinib-resistant BGC-823/R were cultured for determining the effects of (S)-crizotinib on cell viability, apoptosis, oxidant generation, and cell cycle progression. Involvement of ROS, Akt signaling, MTH1, and DNA damage was tested with respective pharmacological blockade. The in vivo anti-tumor effects of (S)-crizotinib were determined using xenograft tumor mice. Results indicated that (S)-crizotinib decreased GC cell viability, induced growth arrest and apoptosis, and increased levels of γH2AX and Ser1981-phosphorylated ATM, which were inhibited by NAC. The anti-cancer mechanism of (S)-crizotinib was independent of MTH1. Moreover, ATM-activated Akt, a pro-survival signal, whose inhibition further enhanced (S)-crizotinib-induced inhibition of GC cell growth and tumor growth in xenograft mice, and re-sensitized resistant GC cells to (S)-crizotinib. (S)-crizotinib reduced GC cell and tumor growth through oxidative DNA damage mechanism and triggered pro-survival Akt signaling. We conclude that inclusion of Akt inhibition (to block the survival signaling) with (S)-crizotinib may provide an effective and novel combination therapy for GC in the clinical setting.

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Preventing Damage Limitation: Targeting DNA-PKcs and DNA Double-Strand Break Repair Pathways for Ovarian Cancer Therapy

Cited by 29 publications

References 98 publications

Knockdown of BRCA2 enhances cisplatin and cisplatin-induced autophagy in ovarian cancer cells

Knockdown of BRCA2 enhances cisplatin and cisplatin-induced autophagy in ovarian cancer cells

Insight into the role of PIKK family members and NF-кB in DNAdamage-induced senescence and senescence-associated secretory phenotype of colon cancer cells

(S)-crizotinib reduces gastric cancer growth through oxidative DNA damage and triggers pro-survival akt signal

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