Up to this point we concluded that GSTP1 affected the s-glutathionylation of PKM2 by increasing the production of lactate in A549 cells, which is also known as the Warburg effect. Anastasiou et al.
described that a low enzyme activity of PKM2 leads to the activation of the pentose phosphate pathway, which ultimately fuels the production of GSH [39]. GSH can than be used in s-glutathionylation reactions by GSTP1, that showed to be excessively expressed in NSCLC tumor and cell lines. To specifically determine whether the s-glutathionylation could modify PKM2 and lead to a lower PKM2 enzyme activity, further analysis has to be carried out. One approach would be to determine PKM2 activity in several NSCLC cell lines that do or do not harbor the KRAS mutation and to further analyze this in tumors obtained from patients that have been diagnosed with NSCLC and are characterized for a KRAS mutation. We also demonstrated that a significant large amount of proteins were glutathionylated. It would therefor be interesting to further identify novel gluthathionylayted proteins using a mass spectrometry approach. This knowledge could provide us with new targetable proteins that could lead to possible new therapeutic implications.
We would also like to utilize the GSTP1/S-glutathionylation status in NSCLC as a diagnostic tool.
The finding that GSTP1 expression and S-glutathionylation are greatly enhanced in NSCLC’s warrant the investigation of the possibility to use this event as a future diagnostic tool and propose GSTP1 as a new biomarker for NSCLC. To elucidate this further we need to characterize tumor tissue obtained from biopsy on their KRAS status and correlate this to GSTP1 expression on overall s-glutathionylation.
The obtained results in this study lets us furthermore conclude that TLK-117 could potentially be a new therapeutic for the treatment of NSCLC. To investigate this further and more into detail it is relevant to gain more knowledge whether inhibition of GSTP1 and S-glutathionylation by TLK-117 in combination with existing chemotherapies such as Carboplatin or Taxol, affects sensitivity or resistance to chemotherapeutics. We would like to propose TLK-117 for stage I clinical trials, but in order to perceive this goal, we need to further show an inhibitory effect on tumorigenesis following pharmacological inhibition of GSTP1.
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