Platinum-induced mitochondrial DNA mutations confer lower sensitivity to paclitaxel by impairing tubulin cytoskeletal organization

Development of chemoresistance is a cogent clinical issue in oncology, whereby combination of anticancer drugs is usually preferred also to enhance efficacy. Paclitaxel (PTX), combined with carboplatin, represents the standard first-line chemotherapy for different types of cancers. We here depict a...

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Bibliographic Details
Published in:Human molecular genetics 2017-08, Vol.26 (15), p.2961-2974
Main Authors: Girolimetti, Giulia, Guerra, Flora, Iommarini, Luisa, Kurelac, Ivana, Vergara, Daniele, Maffia, Michele, Vidone, Michele, Amato, Laura Benedetta, Leone, Giulia, Dusi, Sabrina, Tiranti, Valeria, Perrone, Anna Myriam, Bucci, Cecilia, Porcelli, Anna Maria, Gasparre, Giuseppe
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Carboplatin - metabolism
Cell Line, Tumor
Cytoskeleton - drug effects
DNA, Mitochondrial - drug effects
DNA, Mitochondrial - metabolism
Drug Resistance, Neoplasm - genetics
Female
Humans
Mutation - drug effects
Ovarian Neoplasms - genetics
Paclitaxel - metabolism
Platinum
Tubulin - drug effects
Tubulin - genetics
Tubulin - metabolism
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Summary:Development of chemoresistance is a cogent clinical issue in oncology, whereby combination of anticancer drugs is usually preferred also to enhance efficacy. Paclitaxel (PTX), combined with carboplatin, represents the standard first-line chemotherapy for different types of cancers. We here depict a double-edge role of mitochondrial DNA (mtDNA) mutations induced in cancer cells after treatment with platinum. MtDNA mutations were positively selected by PTX, and they determined a decrease in the mitochondrial respiratory function, as well as in proliferative and tumorigenic potential, in terms of migratory and invasive capacity. Moreover, cells bearing mtDNA mutations lacked filamentous tubulin, the main target of PTX, and failed to reorient the Golgi body upon appropriate stimuli. We also show that the bioenergetic and cytoskeletal phenotype were transferred along with mtDNA mutations in transmitochondrial hybrids, and that this also conferred PTX resistance to recipient cells. Overall, our data show that platinum-induced deleterious mtDNA mutations confer resistance to PTX, and confirm what we previously reported in an ovarian cancer patient treated with carboplatin and PTX who developed a quiescent yet resistant tumor mass harboring mtDNA mutations.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddx186