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  • Mortality from breast cancer is

    2022-05-13

    Mortality from breast cancer is almost always attributed to metastatic spread of the disease to other organs, thus precluding resection as a treatment method. Unfortunately, conventional chemotherapy fails to eradicate most human cancers, including aggressive breast cancers. Studies over the past decade have uncovered certain breast cancer types and cell types that are associated with poor prognosis, such as estrogen/progesterone/HER2 receptor-negative (triple-negative) breast cancers (TNBCs) or cancer stem/precursor cells that possess self-renewing and tumor-initiating capabilities, epithelial-to-mesenchymal transition (EMT), poor prognosis, and chemotherapy resistance within breast tumors (Dawson et al., 2009, Dietze et al., 2015, Polyak and Weinberg, 2009). While eliminating these breast cancer types is critical in combatting breast cancer, there HAMI3379 australia are currently few to no therapies that target this malignant population of breast cancer cells.
    Results
    Discussion Taken together, our data point to GSTP1 as a novel TNBC target that, when inactivated, impairs glycolytic metabolism through a unique mechanism of disrupting GSTP1-induced activation of GAPDH, leading to lower levels of macromolecular building blocks (e.g., lipids and nucleotides) and ATP levels. This reduction in energy levels in turn also leads to impaired oncogenic signaling through activation of AMPK and inhibition of mTOR signaling (Figure 5E). While our interpretations presented here are consistent with the metabolomic and signaling changes that we observe with GSTP1 inactivation in breast cancer cells, we expect that there are also additional mechanisms involved that may arise from the metabolomic changes we observed. For example, we showed increased levels of ACs with GSTP1 inhibition, which we presume to be downstream of ACC inhibition and derepression of CPT1. These results could indicate that fatty HAMI3379 australia β-oxidation pathways may be activated upon GSTP1 inactivation. While we did not observe rescue of cell-survival impairments with the CPT1 inhibitor etomoxir (data not shown), the observed increase in AC levels may play a role in other aspects of GSTP1-mediated effects (Carracedo et al., 2013). GSTP1 has also been linked to many other functions in cancer and other human pathologies and even in drug addiction. Beyond glutathionylation and detoxification functions, GSTP1 has been shown to possess chaperone functions, regulation of nitric oxide pathways, and control over various kinase signaling pathways (Zhang et al., 2014). For example, GSTP1 inhibits JNK signaling and prevents downstream transcriptional activation of cell-stress pathways. Under cellular stress conditions whereby reactive oxygen stress is heightened, GSTP1 has been shown to dimerize into larger aggregates and preclude binding to JNK, enabling JNK activation. In the context of hematopoiesis, GSTP1 inhibition has been shown to play a cytoprotective role in both erythroid and lymphoid cells, and the GSTP1 inhibitor ezatiostat has been shown to be clinically effective for myelodysplastic syndrome (Mahadevan and Sutton, 2015, Zhang et al., 2014). While we report here that GSTP1 inhibition does not activate JNK signaling in our TNBC cells, GSTP1 may still directly regulate other signaling pathways through protein interactions or glutathionylation-mediated pathways (Zhang et al., 2014). We also acknowledge that the apparent activation of GAPDH activity by GSTP1 is only modestly reduced upon LAS17 treatment, indicating that there may be additional complexities involved in the mechanism underlying the GSTP1 induction of GAPDH activity. While our isotopic tracing data clearly indicate that GSTP1 inhibition leads to an impairment in the ATP-generating steps of glycolysis downstream of GAPDH, we do not yet understand the mechanism through which this occurs. GAPDH activity is dependent on a highly reactive catalytic cysteine that coordinates the interconversion between glyceraldehyde-3-phosphate into 1,3-bisphosphoglycerate and is particularly sensitive to oxidation by agents such as hydrogen peroxide or other oxidants that can inhibit GAPDH activity (Hildebrandt et al., 2015). Reports have also shown that GAPDH can even be inhibited by its reactive 1,3-bisphosphoglycerate product on a hyperreactive and functional lysine to inhibit its activity (Moellering and Cravatt, 2013). It would be of future interest to investigate whether GSTP1 interacts with GAPDH to protect hyperreactive sites from being adducted and inhibited. GSTP1 has also been shown to glutathionylate cysteines on proteins to post-translationally regulate protein structure and function and protect proteins from degradation from sulfhydryl overoxidation or proteolysis (Grek et al., 2013). While we were not able to detect GAPDH glutathionylation by GSTP1 and the activation of GAPDH by GSTP1 was independent of GSSG and GSH, it may still be possible that GAPDH activity and glycolytic metabolism may be regulated by GSTP1-mediated glutathionylation. Furthermore, while GAPDH is not generally considered to be a rate-limiting step of glycolysis, a recent study has shown that GAPDH is rate limiting in cancer cells that possess aerobic glycolysis (Hildebrandt et al., 2015, Moellering and Cravatt, 2013, Shestov et al., 2014). Our studies with GSTP1 provide additional support for how GAPDH may act as a major regulatory hub for TNBC glycolytic activity.