Glutaminolysis and glycolysis regulation by troglitazone in breast cancer cells: Relationship to mitochondrial membrane potential
✍ Scribed by Ellen Friday; Robert Oliver III; Tomas Welbourne; Francesco Turturro
- Publisher
- John Wiley and Sons
- Year
- 2010
- Tongue
- English
- Weight
- 351 KB
- Volume
- 226
- Category
- Article
- ISSN
- 0021-9541
No coin nor oath required. For personal study only.
✦ Synopsis
We studied the roles of glycolysis and glutaminolysis following an acute reduction in mitochondrial membrane potential (C m ) induced by the thiazolidinedione troglitazone (TRO) and compared the responses with CCCP-induced depolarization in breast cancer derived MCF-7 and MDA-MB-231 cells as well as in the MCF-10A normal breast cell line. TRO and CCCP both acutely reduced C m but after 24 h TRO-treated cells had restored C m associated with both increased glycolysis and glutaminolysis. In contrast, CCCP-treated cells exhibited only a partial restoration of C m associated with increased glycolysis but decreased glutaminolysis. TRO-induced glutaminolysis was coupled to increased ammonium (GDH flux) and decreased alanine production (ALT flux) in all three cell lines. Both cancer cell lines exhibited a higher spontaneous GDH/ALT flux than the normal breast cell line associated with a reduced keto-acid pool. TRO's effect on GDH/ALT fluxes and mitochondrial keto-acid pool homeostasis was additive with glucose withdrawal suggesting limited intramitochondrial pyruvate availability. The TRO-induced acceleration in GDH flux supplies substrate for Complex I contributing to the restoration of C m as well as Krebs cycle intermediates for biosynthesis. Inhibiting mitochondrial proton ATPase with oligomycin or nullifying the proton gradient with CCCP prevented both the TRO-induced recovery of C m and accelerated GDH flux but restored ALT flux consonant with important roles for proton pumping in regulating GDH flux and C m recovery. Blocking enhanced GDH flux reduced DNA synthesis consistent with glutaminolysis via GDH playing an important biosynthetic role in tumorigenesis.