European mtDNA Variants Are Associated With Differential Responses to Cisplatin, an Anticancer Drug: Implications for Drug Resistance and Side Effects
Background: Cisplatin, a powerful antitumor agent, causes formation of DNA adducts, and activation of apoptotic pathways. Presently, cisplatin resistance develops in up to 70% of patients but the underlying molecular mechanism(s) are unclear and there are no markers to determine which patients will...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-07-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2019.00640/full |
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doaj-5ec2b421a256417c8358fc231cbeb719 |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Tej H. Patel Lucas Norman Steven Chang Sina Abedi Catherine Liu Catherine Liu Marilyn Chwa Shari R. Atilano Kunal Thaker Stephanie Lu Stephanie Lu S. Michal Jazwinski Michael V. Miceli Nitin Udar Daniela Bota M. Cristina Kenney M. Cristina Kenney |
| spellingShingle |
Tej H. Patel Lucas Norman Steven Chang Sina Abedi Catherine Liu Catherine Liu Marilyn Chwa Shari R. Atilano Kunal Thaker Stephanie Lu Stephanie Lu S. Michal Jazwinski Michael V. Miceli Nitin Udar Daniela Bota M. Cristina Kenney M. Cristina Kenney European mtDNA Variants Are Associated With Differential Responses to Cisplatin, an Anticancer Drug: Implications for Drug Resistance and Side Effects Frontiers in Oncology cisplatin mitochondria cybrids drug resistance mtDNA haplogroups |
| author_facet |
Tej H. Patel Lucas Norman Steven Chang Sina Abedi Catherine Liu Catherine Liu Marilyn Chwa Shari R. Atilano Kunal Thaker Stephanie Lu Stephanie Lu S. Michal Jazwinski Michael V. Miceli Nitin Udar Daniela Bota M. Cristina Kenney M. Cristina Kenney |
| author_sort |
Tej H. Patel |
| title |
European mtDNA Variants Are Associated With Differential Responses to Cisplatin, an Anticancer Drug: Implications for Drug Resistance and Side Effects |
| title_short |
European mtDNA Variants Are Associated With Differential Responses to Cisplatin, an Anticancer Drug: Implications for Drug Resistance and Side Effects |
| title_full |
European mtDNA Variants Are Associated With Differential Responses to Cisplatin, an Anticancer Drug: Implications for Drug Resistance and Side Effects |
| title_fullStr |
European mtDNA Variants Are Associated With Differential Responses to Cisplatin, an Anticancer Drug: Implications for Drug Resistance and Side Effects |
| title_full_unstemmed |
European mtDNA Variants Are Associated With Differential Responses to Cisplatin, an Anticancer Drug: Implications for Drug Resistance and Side Effects |
| title_sort |
european mtdna variants are associated with differential responses to cisplatin, an anticancer drug: implications for drug resistance and side effects |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Oncology |
| issn |
2234-943X |
| publishDate |
2019-07-01 |
| description |
Background: Cisplatin, a powerful antitumor agent, causes formation of DNA adducts, and activation of apoptotic pathways. Presently, cisplatin resistance develops in up to 70% of patients but the underlying molecular mechanism(s) are unclear and there are no markers to determine which patients will become resistant. Mitochondria play a significant role not only in energy metabolism but also retrograde signaling (mitochondria to nucleus) that modulates inflammation, complement, and apoptosis pathways. Maternally inherited mitochondrial (mt) DNA can be classified into haplogroups representing different ethnic populations that have diverse susceptibilities to diseases and medications.Methods: Transmitochondrial cybrids, where all cell lines possess identical nuclear genomes but either the H (Southern European) or J (Northern European) mtDNA haplogroups, were treated with cisplatin and analyzed for differential responses related to viability, oxidative stress, and expression levels of genes associated with cancer, cisplatin-induced nephrotoxicity and resistance, apoptosis and signaling pathways.Results: The cisplatin-treated-J cybrids showed greater loss of cell viability along with lower levels of reactive oxygen species and mitochondrial membrane potential compared to cisplatin-treated-H cybrids. After cisplatin treatment, J cybrids showed increased gene expression of BAX, CASP3, and CYP51A, but lower levels of SFRP1 compared to untreated-J cybrids. The cisplatin-treated-H cybrids had elevated expression of CDKN1A/P21, which has a role in cisplatin toxicity, compared to untreated-H cybrids. The cisplatin-treated H had higher transcription levels of ABCC1, DHRS2/HEP27, and EFEMP1 compared to cisplatin-treated-J cybrids.Conclusions: Cybrid cell lines that contain identical nuclei but either H mtDNA mitochondria or J mtDNA mitochondria respond differently to cisplatin treatments suggesting involvement of the retrograde signaling (from mitochondria to nucleus) in the drug-induced cell death. Varying toxicities and transcription levels of the H vs. J cybrids after cisplatin treatment support the hypothesis that mtDNA variants play a role in the expression of genes affecting resistance and side effects of cisplatin. |
| topic |
cisplatin mitochondria cybrids drug resistance mtDNA haplogroups |
| url |
https://www.frontiersin.org/article/10.3389/fonc.2019.00640/full |
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doaj-5ec2b421a256417c8358fc231cbeb7192020-11-24T20:53:57ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2019-07-01910.3389/fonc.2019.00640442046European mtDNA Variants Are Associated With Differential Responses to Cisplatin, an Anticancer Drug: Implications for Drug Resistance and Side EffectsTej H. Patel0Lucas Norman1Steven Chang2Sina Abedi3Catherine Liu4Catherine Liu5Marilyn Chwa6Shari R. Atilano7Kunal Thaker8Stephanie Lu9Stephanie Lu10S. Michal Jazwinski11Michael V. Miceli12Nitin Udar13Daniela Bota14M. Cristina Kenney15M. Cristina Kenney16Gavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United StatesGavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United StatesGavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United StatesGavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United StatesGavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United StatesIllinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, IL, United StatesGavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United StatesGavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United StatesGavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United StatesGavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United StatesVA Medical Center Long Beach Hospital, Long Beach, CA, United StatesTulane Center for Aging and Department of Medicine, Tulane University, New Orleans, LA, United StatesTulane Center for Aging and Department of Medicine, Tulane University, New Orleans, LA, United StatesGavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United StatesDepartment of Neurology, Neuro-Oncology Division, University of California, Irvine, Irvine, CA, United StatesGavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United StatesDepartment of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, United StatesBackground: Cisplatin, a powerful antitumor agent, causes formation of DNA adducts, and activation of apoptotic pathways. Presently, cisplatin resistance develops in up to 70% of patients but the underlying molecular mechanism(s) are unclear and there are no markers to determine which patients will become resistant. Mitochondria play a significant role not only in energy metabolism but also retrograde signaling (mitochondria to nucleus) that modulates inflammation, complement, and apoptosis pathways. Maternally inherited mitochondrial (mt) DNA can be classified into haplogroups representing different ethnic populations that have diverse susceptibilities to diseases and medications.Methods: Transmitochondrial cybrids, where all cell lines possess identical nuclear genomes but either the H (Southern European) or J (Northern European) mtDNA haplogroups, were treated with cisplatin and analyzed for differential responses related to viability, oxidative stress, and expression levels of genes associated with cancer, cisplatin-induced nephrotoxicity and resistance, apoptosis and signaling pathways.Results: The cisplatin-treated-J cybrids showed greater loss of cell viability along with lower levels of reactive oxygen species and mitochondrial membrane potential compared to cisplatin-treated-H cybrids. After cisplatin treatment, J cybrids showed increased gene expression of BAX, CASP3, and CYP51A, but lower levels of SFRP1 compared to untreated-J cybrids. The cisplatin-treated-H cybrids had elevated expression of CDKN1A/P21, which has a role in cisplatin toxicity, compared to untreated-H cybrids. The cisplatin-treated H had higher transcription levels of ABCC1, DHRS2/HEP27, and EFEMP1 compared to cisplatin-treated-J cybrids.Conclusions: Cybrid cell lines that contain identical nuclei but either H mtDNA mitochondria or J mtDNA mitochondria respond differently to cisplatin treatments suggesting involvement of the retrograde signaling (from mitochondria to nucleus) in the drug-induced cell death. Varying toxicities and transcription levels of the H vs. J cybrids after cisplatin treatment support the hypothesis that mtDNA variants play a role in the expression of genes affecting resistance and side effects of cisplatin.https://www.frontiersin.org/article/10.3389/fonc.2019.00640/fullcisplatinmitochondriacybridsdrug resistancemtDNA haplogroups |