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Cisplatin selects short forms of the mitochondrial DNA OriB variant (16184 – 16193 poly-cytosine tract), which confer resistance to cisplatin

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ABSTRACT

A number of alternations in mitochondrial DNA (mtDNA) have been reported in different types of cancers, and the role of mtDNA in cancer has been attracting increasing interest. In order to investigate the relationship between mtDNA alternations and chemosensitivity, we constructed cybrid (trans-mitochondrial hybrid) cell lines carrying a HeLa nucleus and the mtDNA of healthy individuals because of the presence of somatic alternations in the mtDNA of many cancer cells. After a treatment with 1.0 μg/mL cisplatin for 10 days, we isolated 100 cisplatin-resistant clones, 70 of which carried the shorter mtDNA OriB variant (16184–16193 poly-cytosine tract), which was located in the control region of mtDNA. Whole mtDNA sequencing of 10 clones revealed no additional alternations. Re-construction of the HeLa nucleus and mtDNA from cisplatin-resistant cells showed that cisplatin resistance was only acquired by mtDNA alternations in the control region, and not by possible alternation(s) in the nuclear genome.

No MeSH data available.


Survival of 9W4 and R13 cybrids exposed to anti-cancer drugs (cisplatin or 5-FU).(A) 0.4 μg/mL of cisplatin, (B) 1.0 μg/mL of cisplatin, (C) 2.5 μg/mL of cisplatin, (D) 30 μg/mL of 5-FU, and (E) 100 μg/mL of 5-FU. The cell survival fraction is given as a percentage of the respective untreated control. Closed symbols, 9W4 cybrid; open symbols, R13 cybrid. Error bars indicate S.E.M. (n = 3). *P < 0.05; **P < 0.01.
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f4: Survival of 9W4 and R13 cybrids exposed to anti-cancer drugs (cisplatin or 5-FU).(A) 0.4 μg/mL of cisplatin, (B) 1.0 μg/mL of cisplatin, (C) 2.5 μg/mL of cisplatin, (D) 30 μg/mL of 5-FU, and (E) 100 μg/mL of 5-FU. The cell survival fraction is given as a percentage of the respective untreated control. Closed symbols, 9W4 cybrid; open symbols, R13 cybrid. Error bars indicate S.E.M. (n = 3). *P < 0.05; **P < 0.01.

Mentions: In order to confirm the cisplatin sensitivities of the isolated resistant clones, R13 and 9W4 cybrids were cultivated in medium containing cisplatin (Fig. 4A–C). Significant cell survival differences were observed after 2 or 3 days. However, no significant differences were noted in cell survival with the 5-FU treatment (Fig. 4D and E).


Cisplatin selects short forms of the mitochondrial DNA OriB variant (16184 – 16193 poly-cytosine tract), which confer resistance to cisplatin
Survival of 9W4 and R13 cybrids exposed to anti-cancer drugs (cisplatin or 5-FU).(A) 0.4 μg/mL of cisplatin, (B) 1.0 μg/mL of cisplatin, (C) 2.5 μg/mL of cisplatin, (D) 30 μg/mL of 5-FU, and (E) 100 μg/mL of 5-FU. The cell survival fraction is given as a percentage of the respective untreated control. Closed symbols, 9W4 cybrid; open symbols, R13 cybrid. Error bars indicate S.E.M. (n = 3). *P < 0.05; **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5385546&req=5

f4: Survival of 9W4 and R13 cybrids exposed to anti-cancer drugs (cisplatin or 5-FU).(A) 0.4 μg/mL of cisplatin, (B) 1.0 μg/mL of cisplatin, (C) 2.5 μg/mL of cisplatin, (D) 30 μg/mL of 5-FU, and (E) 100 μg/mL of 5-FU. The cell survival fraction is given as a percentage of the respective untreated control. Closed symbols, 9W4 cybrid; open symbols, R13 cybrid. Error bars indicate S.E.M. (n = 3). *P < 0.05; **P < 0.01.
Mentions: In order to confirm the cisplatin sensitivities of the isolated resistant clones, R13 and 9W4 cybrids were cultivated in medium containing cisplatin (Fig. 4A–C). Significant cell survival differences were observed after 2 or 3 days. However, no significant differences were noted in cell survival with the 5-FU treatment (Fig. 4D and E).

View Article: PubMed Central - PubMed

ABSTRACT

A number of alternations in mitochondrial DNA (mtDNA) have been reported in different types of cancers, and the role of mtDNA in cancer has been attracting increasing interest. In order to investigate the relationship between mtDNA alternations and chemosensitivity, we constructed cybrid (trans-mitochondrial hybrid) cell lines carrying a HeLa nucleus and the mtDNA of healthy individuals because of the presence of somatic alternations in the mtDNA of many cancer cells. After a treatment with 1.0&thinsp;&mu;g/mL cisplatin for 10 days, we isolated 100 cisplatin-resistant clones, 70 of which carried the shorter mtDNA OriB variant (16184&ndash;16193 poly-cytosine tract), which was located in the control region of mtDNA. Whole mtDNA sequencing of 10 clones revealed no additional alternations. Re-construction of the HeLa nucleus and mtDNA from cisplatin-resistant cells showed that cisplatin resistance was only acquired by mtDNA alternations in the control region, and not by possible alternation(s) in the nuclear genome.

No MeSH data available.