Hooked on fat: the role of lipid synthesis in cancer metabolism and tumour development

Baenke, Franziska; Peck, Barrie; Miess, Heike; Schulze, Almut

doi:10.1242/dmm.011338

Cited by 662 publications

(706 citation statements)

References 111 publications

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“…Together, these observations imply that HspA1A-membrane association would be increased in membrane regions enriched in saturated lipids, such as lipid rafts, and in cellular membranes containing a high number of saturated lipids. These suggestions are consistent with the presence of HspA1A and other Hsp70s at the plasma membrane of stressed and cancer cells, which have increased membrane rigidity (Baenke et al 2013;De Maio 2014;Kirkegaard et al 2010;Lancaster and Febbraio 2005a;Mambula et al 2007;Multhoff 2007;Schilling et al 2009). Fig.…”

Section: Discussionsupporting

confidence: 82%

Biochemical characterization of the interaction between HspA1A and phospholipids

McCallister¹,

Kdeiss²,

Nikolaidis³

2016

Cell Stress and Chaperones

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Seventy-kilodalton heat shock proteins (Hsp70s) are molecular chaperones essential for maintaining cellular homeostasis. Apart from their indispensable roles in protein homeostasis, specific Hsp70s localize at the plasma membrane and bind to specific lipids. The interaction of Hsp70s with lipids has direct physiological outcomes including lysosomal rescue, microautophagy, and promotion of cell apoptosis. Despite these essential functions, the Hsp70-lipid interactions remain largely uncharacterized. In this study, we characterized the interaction of HspA1A, an inducible Hsp70, with five phospholipids. We first used high concentrations of potassium and established that HspA1A embeds in membranes when bound to all anionic lipids tested. Furthermore, we found that protein insertion is enhanced by increasing the saturation level of the lipids. Next, we determined that the nucleotide-binding domain (NBD) of the protein binds to lipids quantitatively more than the substrate-binding domain (SBD). However, for all lipids tested, the full-length protein is necessary for embedding. We also used calcium and reaction buffers equilibrated at different pH values and determined that electrostatic interactions alone may not fully explain the association of HspA1A with lipids. We then determined that lipid binding is inhibited by nucleotide-binding, but it is unaffected by protein-substrate binding. These results suggest that the HspA1A lipid-association is specific, depends on the physicochemical properties of the lipid, and is mediated by multiple molecular forces. These mechanistic details of the Hsp70-lipid interactions establish a framework of possible physiological functions as they relate to chaperone regulation and localization.

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Section: Discussionsupporting

confidence: 82%

Biochemical characterization of the interaction between HspA1A and phospholipids

McCallister¹,

Kdeiss²,

Nikolaidis³

2016

Cell Stress and Chaperones

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“…Glioblastoma spheroids harbor hypoxic cores where metabolic pathways, including those involving lipids, are changed [4,[83][84][85]. De novo lipogenesis, for instance, was shown to be bypassed in cancer cells in hypoxic conditions.…”

Section: Discussionmentioning

confidence: 99%

“…Although otherwise highly heterogeneous, most cancer types present a lipogenic phenotype characterized by the upregulation of key enzymes and transcriptional factors controlling lipid metabolism (e.g. Akt, fatty acid synthase, hypoxia-inducible factor 1-alpha, sterol regulatory element binding proteins, acetyl-CoA carboxylase alpha), and a boost in de novo lipogenesis [2][3][4][5]. In solid malignancies, the hypoxic conditions found at the core of the tumors induce adaptive pathways aimed at maintaining lipid synthesis, homeostatic pH and cell survival [6].…”

Section: Introductionmentioning

confidence: 99%

Pharmacological inhibition of lipid droplet formation enhances the effectiveness of curcumin in glioblastoma

Zhang

Cui

Amiri

et al. 2016

European Journal of Pharmaceutics and Biopharmaceutics

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a b s t r a c tIncreased lipid droplet number and fatty acid synthesis allow glioblastoma multiforme, the most common and aggressive type of brain cancer, to withstand accelerated metabolic rates and resist therapeutic treatments. Lipid droplets are postulated to sequester hydrophobic therapeutic agents, thereby reducing drug effectiveness. We hypothesized that the inhibition of lipid droplet accumulation in glioblastoma cells using pyrrolidine-2, a cytoplasmic phospholipase A2 alpha inhibitor, can sensitize cancer cells to the killing effect of curcumin, a promising anticancer agent isolated from the turmeric spice. We observed that curcumin localized in the lipid droplets of human U251N glioblastoma cells. Reduction of lipid droplet number using pyrrolidine-2 drastically enhanced the therapeutic effect of curcumin in both 2D and 3D glioblastoma cell models. The mode of cell death involved was found to be mediated by caspase-3. Comparatively, the current clinical chemotherapeutic standard, temozolomide, was significantly less effective in inducing glioblastoma cell death. Together, our results suggest that the inhibition of lipid droplet accumulation is an effective way to enhance the chemotherapeutic effect of curcumin against glioblastoma multiforme.

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“…3,4 In addition, lipid biosynthesis is altered in cancer cells, thus affecting the lipid species present. [5][6][7] In fact, it has been shown that tumors not only harbor structurally different lipids compared to normal cells, but also, in several cases, accumulate fatty acids, cholesterol, and phospholipid species. [5][6][7] Thus, it is plausible that self-lipid-reactive T cells could contribute to antitumor immunity through either recognizing novel tumor lipids or responding to accumulated self-lipids.…”

Section: Introductionmentioning

confidence: 99%

CD1b-autoreactive T cells recognize phospholipid antigens and contribute to antitumor immunity against a CD1b⁺T cell lymphoma

Bagchi

Wang

2016

OncoImmunology

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Adoptive immunotherapy for cancer treatment is an emerging field of study. Till now, several tumorderived, peptide-specific T cell responses have been harnessed for treating cancers. However, the contribution of lipid-specific T cells in tumor immunity has been understudied. CD1 molecules, which present self-and foreign lipid antigens to T cells, are divided into group 1 (CD1a, CD1b, and CD1c) and group 2 (CD1d). Although the role of CD1d-restricted natural killer T cells (NKT) in several tumor models has been well established, the contribution of group 1 CD1-restricted T cells in tumor immunity remains obscure due to the lack of group 1 CD1 expression in mice. In this study, we used a double transgenic mouse model expressing human group 1 CD1 molecules (hCD1Tg) and a CD1b-restricted, self-lipid reactive T cell receptor (HJ1Tg) to study the potential role of group 1 CD1-restricted autoreactive T cells in antitumor response. We found that HJ1 T cells recognized phospholipids and responded more potently to lipid extracted from tumor cells than the equivalent amount of lipids extracted from normal cells. Additionally, the autoreactivity of HJ1 T cells was enhanced upon treatment with various intracellular tolllike receptor (TLR) agonists, including CpG oligodeoxynucleotides (ODN), R848, and poly (I:C). Interestingly, the adoptive transfer of HJ1 T cells conferred protection against the CD1b-transfected murine T cell lymphoma (RMA-S/CD1b) and CpG ODN enhanced the antitumor effect. Thus, this study, for the first time, demonstrates the antitumor potential of CD1b-autoreactive T cells and their potential use in adoptive immunotherapy.

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Hooked on fat: the role of lipid synthesis in cancer metabolism and tumour development

Cited by 662 publications

References 111 publications

Biochemical characterization of the interaction between HspA1A and phospholipids

Biochemical characterization of the interaction between HspA1A and phospholipids

Pharmacological inhibition of lipid droplet formation enhances the effectiveness of curcumin in glioblastoma

CD1b-autoreactive T cells recognize phospholipid antigens and contribute to antitumor immunity against a CD1b⁺T cell lymphoma

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Hooked on fat: the role of lipid synthesis in cancer metabolism and tumour development

Cited by 662 publications

References 111 publications

Biochemical characterization of the interaction between HspA1A and phospholipids

Biochemical characterization of the interaction between HspA1A and phospholipids

Pharmacological inhibition of lipid droplet formation enhances the effectiveness of curcumin in glioblastoma

CD1b-autoreactive T cells recognize phospholipid antigens and contribute to antitumor immunity against a CD1b+T cell lymphoma

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Product

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CD1b-autoreactive T cells recognize phospholipid antigens and contribute to antitumor immunity against a CD1b⁺T cell lymphoma