Inhibition of glucose-6-phosphate dehydrogenase sensitizes cisplatin-resistant cells to death.
The mechanisms of cisplatin resistance, one of the major limitations of current chemotherapy, has only partially been described. We previously demonstrated that cisplatin-resistant ovarian cancer cells (C13), are characterized by reduced mitochondrial activity and higher glucose-dependency when compared to the cisplatin-sensitive counterpart (2008). In this work we further characterized the role of metabolic transformation in cisplatin resistance. By using transmitochondrial hybrids we show that metabolic reprogramming of cisplatin-resistant cell is not caused by inherent mtDNA mutations. We also found that C13 cells not only present an increased glucose-uptake and consumption, but also exhibit increased expression and enzymatic activity of the Pentose Phosphate pathway (PPP) enzyme Glucose-6-Phosphate Dehydrogenase (G6PDH). Moreover, we show that cisplatin-resistant cells are more sensitive to G6PDH inhibition. Even if the metabolomic fingerprint of ovarian cancer cells remains to be further elucidated, these findings indicate that PPP offers innovative potential targets to overcome cisplatin resistance.
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
Daniela
D
Catanzaro
MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge, UK.
Edoardo
E
Gaude
IRCCS "E. Medea", Conegliano, Italy.
Genny
G
Orso
Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Roma, Italy.
Carla
C
Giordano
Department of Biomedical Sciences, University of Padova, Padova, Italy.
Giulia
G
Guzzo
Department of Biomedical Sciences, University of Padova, Padova, Italy.
Andrea
A
Rasola
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
Eugenio
E
Ragazzi
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
Laura
L
Caparrotta
MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge, UK.
Christian
C
Frezza
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
Monica
M
Montopoli
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004272:DNA, Mitochondrial / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004734:Energy Metabolism / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005947:Glucose / Q000378:metabolism; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
D000970:Antineoplastic Agents; D004272:DNA, Mitochondrial; D004791:Enzyme Inhibitors; D005973:Glutamine; D005954:Glucosephosphate Dehydrogenase; D005947:Glucose; D002945:Cisplatin
PPP; cancer metabolism; cisplatin; drug resistance; transmitochondrial hybrids