TY - JOUR
T1 - MutT Homolog1 has multifaceted role in glioma and is under the apparent orchestration by Hypoxia Inducible factor1 alpha
AU - Bhavya, Bharathan
AU - Easwer, H. V.
AU - Vilanilam, G. C.
AU - Anand, C. R.
AU - Sreelakshmi, K.
AU - Urulangodi, Madhusoodanan
AU - Rajalakshmi, P.
AU - Neena, Issac
AU - Padmakrishnan, C. J.
AU - Menon, Girish R.
AU - Krishnakumar, K.
AU - Deepti, A. N.
AU - Gopala, Srinivas
N1 - Funding Information:
The authors would like to acknowledge all the patients involved in the study. The authors would like to acknowledge Dr. Priya Srinivas and Dr. Cibin TR for their valuable inputs and suggestions towards execution of the study. The authors would also like to thank Prof. Thomas Helleday of Karolinska Institutet, Sweden for kindly gifting the MTH1 inhibitor used in the study. BB would like to thank Department of Science and Technology, India for providing the INSPIRE Fellowship (IF150784). CRA acknowledges Council of Scientific and Industrial Research (09/523(0082)/2014-EMR-1), Government of India for granting Research Fellowship.
Funding Information:
The authors would like to acknowledge all the patients involved in the study. The authors would like to acknowledge Dr. Priya Srinivas and Dr. Cibin TR for their valuable inputs and suggestions towards execution of the study. The authors would also like to thank Prof. Thomas Helleday of Karolinska Institutet, Sweden for kindly gifting the MTH1 inhibitor used in the study. BB would like to thank Department of Science and Technology, India for providing the INSPIRE Fellowship (IF150784). CRA acknowledges Council of Scientific and Industrial Research (09/523(0082)/2014-EMR-1), Government of India for granting Research Fellowship. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - Aims: The study focused on the expression and role of a recent potential cancer therapeutic target protein, MutT Homolog1 (MTH1). MTH1 gets activated in an increased reactive oxygen species (ROS) environment and removes the oxidized nucleotides from the cell. The study aimed to check the role of MTH1 in DNA damage and apoptosis, migration and angiogenesis and also to examine its regulation in glioma. Main methods: The experiments were carried out in human glioma tissue samples and brain tissues of epilepsy patients (non-tumor control). We used two human glioblastomas cell lines, U87MG and U251MG cells. In order to study the role of MTH1 in glioma and to analyze the relation of MTH1 with Hif1α, we have used MTH1 siRNA and Hif1α siRNA respectively. Key findings: We found an increased expression of MTH1 in glioma tissues compared to the non-tumor brain tissues. Correlation analysis revealed that those samples showing reduced expression of MTH1 also had high levels of DNA damage and apoptotic markers, while diminished expression of angiogenesis regulators and levels of migration. MTH1 knockdown in vitro by siRNA in tumor cell lines corroborates the above observation. This justifies the emergence of MTH1 inhibitors as potential first-in-class drugs. Mechanistically, our observations suggest that Hif1α may modulate MTH1 expression. Significance: We found elevated MTH1 expression in glioma irrespective of their grades, while its inhibition affects multiple tumor progression pathways, and that targeting Hif1α could simulate the same.
AB - Aims: The study focused on the expression and role of a recent potential cancer therapeutic target protein, MutT Homolog1 (MTH1). MTH1 gets activated in an increased reactive oxygen species (ROS) environment and removes the oxidized nucleotides from the cell. The study aimed to check the role of MTH1 in DNA damage and apoptosis, migration and angiogenesis and also to examine its regulation in glioma. Main methods: The experiments were carried out in human glioma tissue samples and brain tissues of epilepsy patients (non-tumor control). We used two human glioblastomas cell lines, U87MG and U251MG cells. In order to study the role of MTH1 in glioma and to analyze the relation of MTH1 with Hif1α, we have used MTH1 siRNA and Hif1α siRNA respectively. Key findings: We found an increased expression of MTH1 in glioma tissues compared to the non-tumor brain tissues. Correlation analysis revealed that those samples showing reduced expression of MTH1 also had high levels of DNA damage and apoptotic markers, while diminished expression of angiogenesis regulators and levels of migration. MTH1 knockdown in vitro by siRNA in tumor cell lines corroborates the above observation. This justifies the emergence of MTH1 inhibitors as potential first-in-class drugs. Mechanistically, our observations suggest that Hif1α may modulate MTH1 expression. Significance: We found elevated MTH1 expression in glioma irrespective of their grades, while its inhibition affects multiple tumor progression pathways, and that targeting Hif1α could simulate the same.
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U2 - 10.1016/j.lfs.2020.118673
DO - 10.1016/j.lfs.2020.118673
M3 - Article
C2 - 33130078
AN - SCOPUS:85095564576
SN - 0024-3205
VL - 264
JO - Life Sciences
JF - Life Sciences
M1 - 118673
ER -
