Targeting FOXO3a and Sirtuins in breast cancer

SIRT proteins play an important role in the survival and drug resistance of tumour cells, especially during chemotherapy. In this study, we investigated the potency, specificity and cellular targets of three recently identified SIRT inhibitors, Sirtinol, Salermide and EX527. Our results identify the specificity and cellular targets of these novel inhibitors, and suggest that SIRT inhibitors require combined targeting of both SIRT1 and SIRT2 to induce p53 acetylation and cell death in breast cancer cells. Assessing the role of sirtuins in chemoresistance, cisplatin resistant cell lines were developed and characterized. Cisplatin resistant cells (CisR) were found to have higher levels of SIRT1, repressing the activation of FOXO3a. MCF-7 cells overexpressing SIRT1 were also shown to be protected against cisplatin treatment, highlighting its role in resistance. Sirtuins have many cellular targets, including alpha-tubulin, PARP, ku70 and FOXO3a. Because of the similarities between the regulation of p53 and FOXO3a, we decided to elucidate the effect of sirtinol treatment on FOXO3a. Sirtinol treatment was shown to stabilize FOXO3a, similar to its effect on p53, but at lower concentrations. We have shown previously that FOXO3a is an important downstream mediator of the cytotoxicity of receptor tyrosine kinase targeted therapies. To examine the conjecture whether sirtuin inhibitors could increase the proapoptotic potency of lapatinib through stabilization of FOXO3a, lapatinib was treated alone and in combination with sirtinol and EX527. Sirtinol was found to synergise with lapatinib treatment (in cells containing mutant p53) and this was dependent on the presence of FOXO proteins, highlighting the use of sirtuin inhibitors in increasing the efficacy of therapies that indirectly target FOXO3a

Neither Shoreditch nor Manhattan: Post-politics, 'soft austerity urbanism' and real abstraction in Glasgow North

Speirs Locks is being re-constructed as a new cultural quarter in Glasgow North, with urban boosters envisioning the unlikely, rundown and de-populated light industrial estate as a key site in the city's ongoing cultural regeneration strategy. Yet this creative place-making initiative, I argue, masks a post-political conjuncture based on urban speculation, displacement and the foreclosure of dissent. Post-politics at Speirs Locks is characterised by what I term ‘soft austerity urbanism’: seemingly progressive, instrumental small-scale urban catalyst initiatives that in reality complement rather than counter punitive hard austerity urbanism. Relating such processes of soft austerity urbanism to a wider context of state-led gentrification, this study contributes to post-political debates in several ways. Firstly, it questions demands for participation as a proper politics when it has become practically compulsory in contemporary biopolitical capitalism. Secondly, it demonstrates how an extreme economy of austerity urbanism remains the hard underside of post-political, soft austerity urbanism approaches. Thirdly, it illustrates how these approaches relate to wider processes of ‘real abstraction’ – which is no mere flattery of the mind, but instead is rooted in actually existing processes of commodity exchange. Such abstraction, epitomised in the financialisation and privatisation of land and housing, buttresses the same ongoing property dynamics that were so integral to the global financial crisis and ensuing austerity policies in the first place. If we aim to generate a proper politics that creates a genuine rupture with the destructive play of capital in the built environment, the secret of real abstraction must be critically addressed

Sterol regulatory element binding protein-dependent regulation of lipid synthesis supports cell survival and tumor growth.

BACKGROUND: Regulation of lipid metabolism via activation of sterol regulatory element binding proteins (SREBPs) has emerged as an important function of the Akt/mTORC1 signaling axis. Although the contribution of dysregulated Akt/mTORC1 signaling to cancer has been investigated extensively and altered lipid metabolism is observed in many tumors, the exact role of SREBPs in the control of biosynthetic processes required for Akt-dependent cell growth and their contribution to tumorigenesis remains unclear. RESULTS: We first investigated the effects of loss of SREBP function in non-transformed cells. Combined ablation of SREBP1 and SREBP2 by siRNA-mediated gene silencing or chemical inhibition of SREBP activation induced endoplasmic reticulum (ER)-stress and engaged the unfolded protein response (UPR) pathway, specifically under lipoprotein-deplete conditions in human retinal pigment epithelial cells. Induction of ER-stress led to inhibition of protein synthesis through increased phosphorylation of eIF2α. This demonstrates for the first time the importance of SREBP in the coordination of lipid and protein biosynthesis, two processes that are essential for cell growth and proliferation. SREBP ablation caused major changes in lipid composition characterized by a loss of mono- and poly-unsaturated lipids and induced accumulation of reactive oxygen species (ROS) and apoptosis. Alterations in lipid composition and increased ROS levels, rather than overall changes to lipid synthesis rate, were required for ER-stress induction.Next, we analyzed the effect of SREBP ablation in a panel of cancer cell lines. Importantly, induction of apoptosis following SREBP depletion was restricted to lipoprotein-deplete conditions. U87 glioblastoma cells were highly susceptible to silencing of either SREBP isoform, and apoptosis induced by SREBP1 depletion in these cells was rescued by antioxidants or by restoring the levels of mono-unsaturated fatty acids. Moreover, silencing of SREBP1 induced ER-stress in U87 cells in lipoprotein-deplete conditions and prevented tumor growth in a xenograft model. CONCLUSIONS: Taken together, these results demonstrate that regulation of lipid composition by SREBP is essential to maintain the balance between protein and lipid biosynthesis downstream of Akt and to prevent resultant ER-stress and cell death. Regulation of lipid metabolism by the Akt/mTORC1 signaling axis is required for the growth and survival of cancer cells

Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress

A functional genomics study revealed that the activity of acetyl-CoA synthetase 2 (ACSS2) contributes to cancer cell growth under low-oxygen and lipid-depleted conditions. Comparative metabolomics and lipidomics demonstrated that acetate is used as a nutritional source by cancer cells in an ACSS2-dependent manner, and supplied a significant fraction of the carbon within the fatty acid and phospholipid pools. ACSS2 expression is upregulated under metabolically stressed conditions and ACSS2 silencing reduced the growth of tumor xenografts. ACSS2 exhibits copy-number gain in human breast tumors, and ACSS2 expression correlates with disease progression. These results signify a critical role for acetate consumption in the production of lipid biomass within the harsh tumor microenvironment

Fatty acid uptake and lipid storage induced by HIF-1α contribute to cell growth and survival after hypoxia-reoxygenation.

An in vivo model of antiangiogenic therapy allowed us to identify genes upregulated by bevacizumab treatment, including Fatty Acid Binding Protein 3 (FABP3) and FABP7, both of which are involved in fatty acid uptake. In vitro, both were induced by hypoxia in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. There was a significant lipid droplet (LD) accumulation in hypoxia that was time and O2 concentration dependent. Knockdown of endogenous expression of FABP3, FABP7, or Adipophilin (an essential LD structural component) significantly impaired LD formation under hypoxia. We showed that LD accumulation is due to FABP3/7-dependent fatty acid uptake while de novo fatty acid synthesis is repressed in hypoxia. We also showed that ATP production occurs via β-oxidation or glycogen degradation in a cell-type-dependent manner in hypoxia-reoxygenation. Finally, inhibition of lipid storage reduced protection against reactive oxygen species toxicity, decreased the survival of cells subjected to hypoxia-reoxygenation in vitro, and strongly impaired tumorigenesis in vivo

The glutathione redox system is essential to prevent ferroptosis caused by impaired lipid metabolism in clear cell renal cell carcinoma

The publisher's final edited version of this article is available at Oncogene. 2018 Oct;37(40):5435-5450. doi: 10.1038/s41388-018-0315-z. Epub 2018 Jun 5. Non-commercial use onlyThis study was funded by Cancer Research UK, the German Research Foundation (FOR2314) and the German Cancer Aid (111917)