Abstract
The idea of using metabolic aberrations as targets for diagnosis or therapeutic intervention has recently gained increasing interest. In a previous study, our group discovered intriguing differences in the oxidative mitochondrial respiration capacity of benign and prostate cancer (PCa) cells. In particular, we found that PCa cells had a higher total respiratory activity than benign cells. Moreover, PCa cells showed a substantial shift towards succinate-supported mitochondrial respiration compared to benign cells, indicating a re-programming of respiratory control. This study aimed to investigate the role of succinate and its main plasma membrane transporter NaDC3 (sodium-dependent dicarboxylate transporter member 3) in PCa cells and to determine whether targeting succinate metabolism can be potentially used to inhibit PCa cell growth. Using high-resolution respirometry analysis, we observed that ROUTINE respiration in viable cells and succinate-supported respiration in permeabilized cells was higher in cells lacking the tumor suppressor phosphatase and tensin-homolog deleted on chromosome 10 (PTEN), which is frequently lost in PCa. In addition, loss of PTEN was associated with increased intracellular succinate accumulation and higher expression of NaDC3. However, siRNA-mediated knockdown of NaDC3 only moderately influenced succinate metabolism and did not affect PCa cell growth. By contrast, mersalyl acid—a broad acting inhibitor of dicarboxylic acid carriers—strongly interfered with intracellular succinate levels and resulted in reduced numbers of PCa cells. These findings suggest that blocking NaDC3 alone is insufficient to intervene with altered succinate metabolism associated with PCa. In conclusion, our data provide evidence that loss of PTEN is associated with increased succinate accumulation and enhanced succinate-supported respiration, which cannot be overcome by inhibiting the succinate transporter NaDC3 alone.
Highlights
TuTmuomrocrecllesllasraerkenkonwownntotoaaddaapptttthheeiirrmmeettaabboolliissmm iinnoorrddeerrtotosusustsatianina ahihgihghprporliofleirfaetriavteivceapcaacpiatycity desdpeistpeitceoncodnitdioitniosnosforfedreudcuecdedavaavilaaiblaibliitlyityofoofxoyxgyegnenanadndnunturtireinetnstsininthtehetutmumorormmicircoreonenvvirioronnmmeenntt[1]
To determine whether loss of phosphatase and tensin-homolog deleted on chromosome 10 (PTEN) has an impact on the cellular respiratory capacity, we analyzed a murine prostate cell line that was created from a Pten knockout (KO) mouse (JP11066) and compared its respiratory activity to that of prostate cells established from a Pten wildtype (WT) mouse (JP5038)
Earlier findings by us and others provided considerable evidence that succinate metabolism plays an important role in prostate cancer (PCa) [4,5,7,13]
Summary
TuTmuomrocrecllesllasraerkenkonwownntotoaaddaapptttthheeiirrmmeettaabboolliissmm iinnoorrddeerrtotosusustsatianina ahihgihghprporliofleirfaetriavteivceapcaacpiatycity desdpeistpeitceoncodnitdioitniosnosforfedreudcuecdedavaavilaaiblaibliitlyityofoofxoyxgyegnenanadndnunturtireinetnstsininthtehetutmumorormmicircoreonenvvirioronnmmeenntt[1]. By scrutinizing the respiratory capacity of pathways through the different segments (complexes CI–CIII–CIV or complexes CII–CIII–CIV) of the electron transfer system (ETS) (Figure 1A), we observed that PCa cells showed a substantial shift towards succinate-supported oxidation via mitochondrial Complex II (CII) compared to benign cells [4]. This shift from NADH- to the succinate-linked pathway (CII) was observed in primary PCa tissue in vivo [5], indicating a functional re-programming of ETS. We investigated the role of succinate and its transporter, NaDC3, in PCa cells and evaluated the suitability of NaDC3 as a possible target for PCa therapy
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