Sustained inhibition of PARP-1 activity delays glioblastoma recurrence by enhancing radiation-induced senescence

Ghorai, Atanu; Mahaddalkar, Tejashree; Thorat, Rahul; Dutt, Shilpee

doi:10.1016/j.canlet.2020.06.023

Cited by 37 publications

(24 citation statements)

References 49 publications

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“…Senescence associated-β-galactosidase activity assay U87 and SF268 cells were seeded into 6-well plates and treated with 100 µg/ ml ciprofloxacin for 5, 10 or 15 days. Senescence Associated-β-galactosidase (SA-β-gal) activity assay was performed using a protocol published by Ghorai et al (2020). Cells were viewed using a Leica microscope (20×) and analyzed using Q-capture pro software.…”

Section: Morphological Changesmentioning

confidence: 99%

Nuclear localization of p65 reverses therapy-induced senescence

Salunkhe

Mishra

Nair

et al. 2021

Journal of Cell Science

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Senescence is a tumor suppressor phenomenon. We have earlier shown that therapy induced senescence in residual disease glioblastoma (GBM) cells can reverse leading to relapse. Here we demonstrate that ciprofloxacin induced senescence in glioma-derived cell lines and primary cultures defined by β-gal positivity, SASP release, giant-cell formation, higher ROS, p-ATM, γ-H2AX, and senescence gene signature have three stages- initiation, pseudo-senescence and permanent-senescence. Drug withdrawal during initiation and pseudo-senescence reinitiated proliferation in vitro and tumor formation in vivo. Importantly, prolonged ciprofloxacin treatment induced permanent-senescence that failed to reverse following drug withdrawal. RNA-Seq revealed downregulated p65 transcription network and incremental SMAD pathway genes expression from initiation to permanent-senescence. Drug withdrawal at initiation and pseudo-senescence but not permanent-senescence increased p65 nuclear localization, and escape from senescence. In contrast, permanent-senescent cells showed loss of nuclear p65 and increased apoptosis. Pharmacological or genetic p65 knockdown upholds senescence in vitro and inhibit tumor formation in vivo. Together, this study demonstrates that levels of nuclear p65 defines the window of therapy induced senescence reversibility and coupling senotherapeutic drugs with p65 inhibitors induce permanent-senescence in GBM cells.

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Section: Morphological Changesmentioning

confidence: 99%

Nuclear localization of p65 reverses therapy-induced senescence

Salunkhe

Mishra

Nair

et al. 2021

Journal of Cell Science

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“…rence rates due to the induction of a tumour-promoting microenvironment[182,[185][186][187]. The DNA damage caused by irradiation results in the induction of senescence and SASP in both tumour cells and/or non-tumour cells in the microenvironment, which as previously discussed can be pro-tumourigenic and lead to recurrence[7,15,52].…”

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confidence: 92%

Cell senescence in neuropathology: A focus on neurodegeneration and tumours

Carreno

Guiho

2021

Neuropathology Appl Neurobio

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Since the initial discovery and description of senescent cells by Hayflick and Moorhead in 1961 [1], the field of senescence has evolved and expanded immensely. Hayflick originally observed that primary human fibroblast cell cultures had a finite proliferative capacity in vitro. This finite proliferative capacity is now termed replicative senescence and is due to the gradual attrition of telomeres over serial passages [2]. It was initially proposed that replicative senescence was the driver of organismal ageing due to the possible lack

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“…Gliomas are the most common primary tumors affecting the adult human central nervous system. The highest-grade form of gliomas, glioblastoma (GBM), accounts for more than 50 % of all diagnosed adult gliomas [ 1 , 2 ]. Despite surgical [ 3 ], chemo-radiotherapeutic [ 4 ], and anti-angiogenic treatment [ 5 ], the median overall survival for patients receiving the standard of care remains poor at approximately 12–15 months [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Cyclin G2 reverses immunosuppressive tumor microenvironment and potentiates PD-1 blockade in glioma

Zhao

Gao

et al. 2021

J Exp Clin Cancer Res

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Background Expression of aberrant cyclin G2 is a key factor contributing to cancer biological processes, including glioma. However, the potential underlying mechanisms of cyclin G2 in the glioma tumor immune microenvironment remain unclear. Methods Co-immunoprecipitation (co-IP), in situ proximity ligation assay (PLA), and in vitro kinase assay were conducted to reveal the underlying mechanism by which cyclin G2 regulates Y10 phosphorylation of LDHA. Further, the biological roles of cyclin G2 in cell proliferation, migration, invasion capacity, apoptosis, glycolysis, and immunomodulation were assessed through in vitro and in vivo functional experiments. Expressions of cyclin G2 and Foxp3 in glioma specimens was determined by immunohistochemistry. Results In this study, we found that cyclin G2 impeded the interaction between LDHA and FGFR1, thereby decreasing Y10 phosphorylation of LDHA through FGFR1 catalysis. Cyclin G2 inhibited proliferation, migration, invasion capacity, and glycolysis and promoted apoptosis glioma cells via suppressing Y10 phosphorylation of LDHA. Moreover, we further verified that cyclin G2 reversed the immunosuppressive to antitumor immune microenvironment through inhibiting lactate production by glioma cells. Besides, cyclin G2 potentiated PD-1 blockade and exerted strong antitumor immunity in the glioma-bearing mice model. Conclusions Cyclin G2 acts as a potent tumor suppressor in glioma and enhances responses to immunotherapy. Our findings may be helpful in selecting glioma patients for immunotherapy trials in the future.

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Sustained inhibition of PARP-1 activity delays glioblastoma recurrence by enhancing radiation-induced senescence

Cited by 37 publications

References 49 publications

Nuclear localization of p65 reverses therapy-induced senescence

Nuclear localization of p65 reverses therapy-induced senescence

Cell senescence in neuropathology: A focus on neurodegeneration and tumours

Cyclin G2 reverses immunosuppressive tumor microenvironment and potentiates PD-1 blockade in glioma

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