Progression of O6-methylguanine-DNA methyltransferase and temozolomide resistance in cancer research

Guan, Jun; Jiang, An; Xin, Yong; Li, Liantao; Qian, Cheng; Zheng, Junnian

doi:10.1007/s11033-014-3549-z

Cited by 17 publications

(12 citation statements)

References 62 publications

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“…O‐6‐methylguanine‐DNA methyltransferase (MGMT) is an enzyme involved in the direct reversal of DNA damage in vitro and postmitotic cells in vivo by methylating agents used clinically for chemotherapy (Iyama & Wilson, 2013; Jiang et al ., 2014). It have been suggested that MGMT may play a role in regulating mouse lifespan (Meira et al ., 2014), but it is not known whether long‐lived mice, such as Snell, GHRKO, and PAPPA‐KO, have altered expression of MGMT.…”

Section: Introductionmentioning

confidence: 99%

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

Dominick

Bowman

et al. 2016

Aging Cell

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SummaryStudies of the mTOR pathway have prompted speculation that diminished mTOR complex‐1 (mTORC1) function may be involved in controlling the aging process. Our previous studies have shown diminished mTORC1 activity in tissues of three long‐lived mutant mice: Snell dwarf mice, growth hormone receptor gene disrupted mice (GHRKO), and in this article, mice deficient in the pregnancy‐associated protein‐A (PAPPA‐KO). The ways in which lower mTOR signals slow aging and age‐related diseases are, however, not well characterized. Here, we show that Snell, GHKRO, and PAPPA‐KO mice express high levels of two proteins involved in DNA repair, O‐6‐methylguanine‐DNA methyltransferase (MGMT) and N‐myc downstream‐regulated gene 1 (NDRG1). Furthermore, we report that lowering mTOR enhances MGMT and NDRG1 protein expression via post‐transcriptional mechanisms. We show that the CCR4‐NOT complex, a post‐transcriptional regulator of gene expression, is downstream of the mTORC1 pathway and may be responsible for the upregulation of MGMT and NDRG1 in all three varieties of long‐lived mice. Our data thus suggest a novel link between DNA repair and mTOR signaling via post‐transcriptional regulation involving specific alteration in the CCR4‐NOT complex, whose modulation could control multiple aspects of the aging process.

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Section: Introductionmentioning

confidence: 99%

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

Dominick

Bowman

et al. 2016

Aging Cell

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“…We next determined if OXA altered expression of the DNA repair enzyme O -6-methylguanine-DNA methyltransferase (MGMT), which is largely responsible for resistance to the GBM standard-of-care chemotherapeutic TMZ [23, 24]. We found that OXA treatment of KR158-luc cells reduced MGMT protein (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…While OXA has been shown previously to induce ER stress leading to ICD [15], this study links OXA-induced ER stress to the inhibition of STAT3 and downregulation of MGMT, highlighting additional and important alternative effects of OXA. MGMT diminishes the effectiveness of TMZ, the standard chemotherapy for GBM, by repairing TMZ-induced DNA damage [23, 24]. As a result, MGMT has become a major therapeutic target for overcoming tumor resistance to the standard GBM treatment [23, 24].…”

Section: Discussionmentioning

confidence: 99%

Oxaliplatin disrupts pathological features of glioma cells and associated macrophages independent of apoptosis induction

et al. 2018

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“…Low/high MGMT expression status is an established risk factor for sensitivity/resistance to temozolomide in glioblastomas [96] . Similarly, in NETs, low MGMT expression [51,52] or MGMT promoter hypermethylation [97] is associated with a higher sensitivity to alkylating chemotherapeutics such as temozolomide.…”

Section: Discussionmentioning

confidence: 99%

The HDM2 (MDM2) Inhibitor NVP-CGM097 Inhibits Tumor Cell Proliferation and Shows Additive Effects with 5-Fluorouracil on the p53-p21-Rb-E2F1 Cascade in the p53<sup>wild type</sup> Neuroendocrine Tumor Cell Line GOT1

et al. 2016

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Background/Aims: The tumor suppressor p53 is depleted in many tumor cells by the E3 ubiquitin ligase mouse double minute 2 homolog (MDM2) through MDM2/p53 interaction. A novel target for inhibiting p53 degradation and for causing reexpression of p53^{wild type} is inhibition of MDM2. The small molecule NVP-CGM097 is a novel MDM2 inhibitor. We investigated MDM2 inhibition as a target in neuroendocrine tumor cells in vitro. Methods: Human neuroendocrine tumor cell lines from the pancreas (BON1), lung (NCI-H727), and midgut (GOT1) were incubated with the MDM2 inhibitor NVP-CGM097 (Novartis) at concentrations from 4 to 2,500 nM. Results: While p53^{wild type} GOT1 cells were sensitive to NVP-CGM097, p53^mutated BON1 and p53^mutated NCI-H727 cells were resistant to NVP-CGM097. Incubation of GOT1 cells with NVP-CGM097 at 100, 500, and 2,500 nM for 96 h caused a significant decline in cell viability to 84.9 ± 9.2% (p < 0.05), 77.4 ± 6.6% (p < 0.01), and 47.7 ± 9.2% (p < 0.01). In a Western blot analysis of GOT1 cells, NVP-CGM097 caused a dose-dependent increase in the expression of p53 and p21 tumor suppressor proteins and a decrease in phospho-Rb and E2F1. Experiments of co-incubation of NVP-CGM097 with 5-fluorouracil, temozolomide, or everolimus each showed additive antiproliferative effects in GOT1 cells. NVP-CGM097 and 5-fluorouracil increased p53 and p21 expression in an additive manner. Conclusions: MDM2 inhibition seems a promising novel therapeutic target in neuroendocrine tumors harboring p53^{wild type}. Further investigations should examine the potential role of MDM2 inhibitors in neuroendocrine tumor treatment.

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Progression of O6-methylguanine-DNA methyltransferase and temozolomide resistance in cancer research

Cited by 17 publications

References 62 publications

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

Oxaliplatin disrupts pathological features of glioma cells and associated macrophages independent of apoptosis induction

The HDM2 (MDM2) Inhibitor NVP-CGM097 Inhibits Tumor Cell Proliferation and Shows Additive Effects with 5-Fluorouracil on the p53-p21-Rb-E2F1 Cascade in the p53<sup>wild type</sup> Neuroendocrine Tumor Cell Line GOT1

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