Reduction of MLH1 and PMS2 confers temozolomide resistance and is associated with recurrence of glioblastoma

Shinsato, Yoshinari; Furukawa, Tatsuhiko; Yunoue, Shunji; Yonezawa, Hajime; Minami, Kentarou; Nishizawa, Yuji; Ikeda, Ryuji; Kawahara, Kohichi; Yamamoto, Masayuki; Hirano, Hirofumi; Tokimura, Hiroshi; Arita, Kazunori

doi:10.18632/oncotarget.1302

Cited by 68 publications

(47 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mechanistically, it mispairs with cytosine or thymine during DNA synthesis in the S phase, and repetitive, futile attempts to remove the mismatch by MMR result in formation of DSBs that induce cell death (46,47). Thus, efficient MMR is required for tumor sensitivity to TMZ (48), and loss of expression of MLH1, a member of the MMR pathway, is associated with resistance of gliomas (49) and medulloblastomas (50) to TMZ. The O 6 MeG lesion is reversed in a stoichiometric manner by methylguanine methyltransferase (MGMT) (51).…”

Section: Dna Methylating Agentsmentioning

confidence: 99%

The DNA Damage Response: Implications for Tumor Responses to Radiation and Chemotherapy

2015

View full text Add to dashboard Cite

Cellular responses to DNA damage are important determinants of both cancer development and cancer outcome following radiation therapy and chemotherapy. Identification of molecular pathways governing DNA damage signaling and DNA repair in response to different types of DNA lesions allows for a better understanding of the effects of radiation and chemotherapy on normal and tumor cells. Although dysregulation of the DNA damage response (DDR) is associated with predisposition to cancer development, it can also result in hypersensitivity or resistance of tumors to therapy and can be exploited for improvement of cancer treatment. We highlight the DDR pathways that are activated after treatment with radiation and different classes of chemotherapeutic drugs and describe mechanisms determining tumor sensitivity and resistance to these agents. Further, we discuss approaches to enhance tumor sensitivity to radiation and chemotherapy by modulating the DDR with a goal of enhancing the effectiveness of cancer therapies.

show abstract

Section: Dna Methylating Agentsmentioning

confidence: 99%

The DNA Damage Response: Implications for Tumor Responses to Radiation and Chemotherapy

2015

View full text Add to dashboard Cite

show abstract

“…The online version of this article (https ://doi.org/10.1007/s1106 0-020-03461 -4) contains supplementary material, which is available to authorized users. 1 3 correlated with higher tumor proliferation rates and poorer survival outcomes [6][7][8].…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

Epigenetic preconditioning with decitabine sensitizes glioblastoma to temozolomide via induction of MLH1

Gallitto

Inocencio

et al. 2020

J Neurooncol

View full text Add to dashboard Cite

Introduction To improve the standard treatment paradigm for glioblastoma (GBM), efforts have been made to explore the efficacy of epigenetic agents as chemosensitizers. Recent data suggest possible synergy between decitabine (DAC), a DNA hypomethylating agent, and temozolomide (TMZ) in GBM, but the mechanism remains unclear. The objective of this study was to determine the effects of DAC on TMZ sensitization in a consecutively derived set of primary GBM cultures, with a focus on mismatch repair (MMR) proteins. Methods Half maximal inhibitory concentrations (IC 50 ) of TMZ were calculated in eleven consecutive patient-derived GBM cell lines before and after preconditioning with DAC. MMR protein expression changes were determined by quantitative immunoblots and qPCR arrays. Single-molecule real-time (SMRT) sequencing of bisulfite (BS)-converted PCR amplicons of the MLH1 promoter was performed to determine methylation status. Results TMZ IC 50 significantly changed in 6 of 11 GBM lines of varying MGMT promoter methylation status in response to DAC preconditioning. Knockdown of MLH1 after preconditioning reversed TMZ sensitization. SMRT-BS sequencing of the MLH1 promoter region revealed higher levels of baseline methylation at proximal CpGs in desensitized lines compared to sensitized lines. Conclusions DAC enhances TMZ cytotoxicity in a subset of GBM cell lines, comprising lines both MGMT methylated and unmethylated tumors. This effect may be driven by levels of MLH1 via E2F1 transcription factor binding. Using unbiased long-range next-generation bisulfite-sequencing, we identified a region of the proximal MLH1 promoter with differential methylation patterns that has potential utility as a clinical biomarker for TMZ sensitization.

show abstract

“…Quantitative reverse transcription PCR was performed as described previously (20). The respective forward and reverse primers' sequences are provided in Supplementary Table 1.…”

Section: Quantitative Reverse Transcription Pcrmentioning

confidence: 99%

Ribonucleotide reductase is an effective target to overcome gemcitabine resistance in gemcitabine-resistant pancreatic cancer cells with dual resistant factors

Minami

Shinsato

Yamamoto

et al. 2015

Journal of Pharmacological Sciences

Self Cite

View full text Add to dashboard Cite

Gemcitabine is widely used for pancreatic, lung, and bladder cancer. However, drug resistance against gemcitabine is a large obstacle to effective chemotherapy. Nucleoside transporters, nucleoside and nucleotide metabolic enzymes, and efflux transporters have been reported to be involved in gemcitabine resistance. Although most of the resistant factors are supposed to be related to each other, it is unclear how one factor can affect the other one. In this study, we established gemcitabine-resistant pancreatic cancer cell lines. Gemcitabine resistance in these cells is caused by two major processes: a decrease in gemcitabine uptake and overexpression of ribonucleotide reductase large subunit (RRM1). Knockdown of RRM1, but not the overexpression of concentrative nucleoside transporter 1 (CNT1), could completely overcome the gemcitabine resistance. RRM1 knockdown in gemcitabine-resistant cells could increase the intracellular accumulation of gemcitabine by increasing the nucleoside transporter expression. Furthermore, a synergistic effect was observed between hydroxyurea, a ribonucleotide reductase (RR) inhibitor, and gemcitabine on the gemcitabine-resistant cells. Here we indicate that RR is one of the most promising targets to overcome gemcitabine resistance in gemcitabine-resistant cells with dual resistant factors.

show abstract

Reduction of MLH1 and PMS2 confers temozolomide resistance and is associated with recurrence of glioblastoma

Cited by 68 publications

References 26 publications

The DNA Damage Response: Implications for Tumor Responses to Radiation and Chemotherapy

The DNA Damage Response: Implications for Tumor Responses to Radiation and Chemotherapy

Epigenetic preconditioning with decitabine sensitizes glioblastoma to temozolomide via induction of MLH1

Ribonucleotide reductase is an effective target to overcome gemcitabine resistance in gemcitabine-resistant pancreatic cancer cells with dual resistant factors

Contact Info

Product

Resources

About