Tamoxifen inhibits malignant peripheral nerve sheath tumor growth in an estrogen receptor-independent manner

Few therapeutic options are available for malignant peripheral nerve sheath tumors (MPNSTs), the most common malignancy associated with neurofibromatosis type 1 (NF1). Guided by clinical observations suggesting that some NF1-associated nerve sheath tumors are hormonally responsive, we hypothesized that the selective estrogen receptor (ER) modulator tamoxifen would inhibit MPNST tumorigenesis in vitro and in vivo. To test this hypothesis, we examined tamoxifen effects on MPNST cell proliferation and survival, MPNST xenograft growth, and the mechanism by which tamoxifen impeded these processes. We found that 1-5 μM 4-hydroxy-tamoxifen induced MPNST cell death, whereas 0.01-0.1 μM 4-hydroxy-tamoxifen inhibited mitogenesis. Dermal and plexiform neurofibromas, MPNSTs, and MPNST cell lines expressed ERβ and G-protein-coupled ER-1 (GPER); MPNSTs also expressed estrogen biosynthetic enzymes. However, MPNST cells did not secrete 17β-estradiol, exogenous 17β-estradiol did not stimulate mitogenesis or rescue 4-hydroxy-tamoxifen effects on MPNST cells, and the steroidal antiestrogen ICI-182,780 did not mimic tamoxifen effects on MPNST cells. Further, ablation of ERβ and GPER had no effect on MPNST proliferation, survival, or tamoxifen sensitivity, indicating that tamoxifen acts via an ER-independent mechanism. Consistent with this hypothesis, inhibitors of calmodulin (trifluoperazine, W-7), another known tamoxifen target, recapitulated 4-hydroxy-tamoxifen effects on MPNST cells. Tamoxifen was also effective in vivo, demonstrating potent antitumor activity in mice orthotopically xenografted with human MPNST cells. We conclude that 4-hydroxy-tamoxifen inhibits MPNST cell proliferation and survival via an ER-independent mechanism. The in vivo effectiveness of tamoxifen provides a rationale for clinical trials in cases of MPNSTs.     

Mitogenic Sonic hedgehog signaling drives E2F1-dependent lipogenesis in progenitor cells and medulloblastoma

Deregulation of the Rb/E2F tumor suppressor complex and aberrantion of Sonic hedgehog (Shh) signaling are documented across the spectrum of human malignancies. Exaggerated de novo lipid synthesis is also found in certain highly proliferative, aggressive tumors. Here, we show that in Shh-driven medulloblastomas, Rb is inactivated and E2F1 is upregulated, promoting lipogenesis. Extensive lipid accumulation and elevated levels of the lipogenic enzyme fatty acid synthase (FASN) mark those tumors. In primary cerebellar granule neuron precursors (CGNPs), proposed Shh-associated medulloblastoma cells-of-origin, Shh signaling triggers E2F1 and FASN expression, whereas suppressing fatty acid oxidation (FAO), in a smoothened-dependent manner. In the developing cerebellum, E2F1 and FASN co-localize in proliferating CGNPs. in vivo and in vitro, E2F1 is required for FASN expression and CGNP proliferation, and E2F1 knockdown impairs Shh-mediated FAO inhibition. Pharmacological blockade of Rb inactivation and/or lipogenesis inhibits CGNP proliferation, drives medulloblastoma cell death and extends survival of medulloblastoma-bearing animals In vivo. These findings identify a novel mechanism through which Shh signaling links cell cycle progression to lipid synthesis, through E2F1-dependent regulation of lipogenic enzymes. These findings pertinent to the etiology of tumor metabolism also underscore the key role of the Shh→E2F1→FASN axis in regulating de novo lipid synthesis in cancers, and as such its value as a global therapeutic target in hedgehog-dependent and/or Rb-inactivated tumors.     

Large-scale molecular comparison of human schwann cells to malignant peripheral nerve sheath tumor cell lines and tissues

Malignant peripheral nerve sheath tumors (MPNST) are highly invasive soft tissue sarcomas that arise within the peripheral nerve and frequently metastasize. To identify molecular events contributing to malignant transformation in peripheral nerve, we compared eight cell lines derived from MPNSTs and seven normal human Schwann cell samples. We found that MPNST lines are heterogeneous in their in vitro growth rates and exhibit diverse alterations in expression of pRb, p53, p14(Arf), and p16(INK4a) proteins. All MPNST cell lines express the epidermal growth factor receptor and lack S100beta protein. Global gene expression profiling using Affymetrix oligonucleotide microarrays identified a 159-gene molecular signature distinguishing MPNST cell lines from normal Schwann cells, which was validated in Affymetrix microarray data generated from 45 primary MPNSTs. Expression of Schwann cell differentiation markers (SOX10, CNP, PMP22, and NGFR) was down-regulated in MPNSTs whereas neural crest stem cell markers, SOX9 and TWIST1, were overexpressed in MPNSTs. Previous studies have implicated TWIST1 in apoptosis inhibition, resistance to chemotherapy, and metastasis. Reducing TWIST1 expression in MPNST cells using small interfering RNA did not affect apoptosis or chemoresistance but inhibited cell chemotaxis. Our results highlight the use of gene expression profiling in identifying genes and molecular pathways that are potential biomarkers and/or therapeutic targets for treatment of MPNST and support the use of the MPNST cell lines as a primary analytic tool.     

Activation of the neuregulin-1/ErbB signaling pathway promotes the proliferation of neoplastic Schwann cells in human malignant peripheral nerve sheath tumors

Patients with neurofibromatosis type 1 develop aggressive Schwann cell neoplasms known as malignant peripheral nerve sheath tumors (MPNSTs). Although tumor suppressor gene mutations play an important role in MPNST pathogenesis, it is likely that dysregulated signaling by as yet unidentified growth factors also contributes to the formation of these sarcomas. To test the hypothesis that neuregulin-1 (NRG-1) growth factors promote mitogenesis in MPNSTs, we examined the expression and action of NRG-1 in human MPNSTs and neurofibromas, the benign precursor lesions from which MPNSTs arise. Multiple alpha and beta transmembrane precursors from the class II and III NRG-1 subfamilies are present in both tumor types. Neoplastic Schwann cells within these neoplasms variably express the erbB kinases mediating NRG-1 responses (erbB2, erbB3 and/or erbB4). Human MPNST cell lines (Mash-1, YST-1, NMS-2 and NMS-2PC cells) similarly coexpress multiple NRG-1 isoforms and erbB receptors. These MPNST lines are NRG-1 responsive and demonstrate constitutive erbB phosphorylation. Treatment with PD168393 and PD158780, two structurally and mechanistically distinct erbB inhibitors, abolishes erbB phosphorylation and reduces DNA synthesis in these lines. These findings suggest that autocrine and/or paracrine NRG-1/erbB signaling promotes neoplastic Schwann cell proliferation and may be an important therapeutic target in neurofibromas and MPNSTs.     

Preclinical in vivo evaluation of rapamycin in human malignant peripheral nerve sheath explant xenograft

Neurofibromatosis type 1 (NF1) patients are prone to the development of malignant tumors, the most common being Malignant Peripheral Nerve Sheath Tumor (MPNST). NF1‐MPNST patients have an overall poor survival due to systemic metastasis. Currently, the management of MPNSTs includes surgery and radiation; however, conventional chemotherapy is not very effective, underscoring the need for effective biologically‐targeted therapies. Recently, the NF1 gene product, neurofibromin, was shown to negatively regulate the phosphoinositide‐3‐kinase (PI3K)/Protein Kinase‐B (Akt)/mammalian Target Of Rapamycin (mTOR) pathway, with loss of neurofibromin expression in established human MPNST cell lines associated with high levels of mTOR activity. We developed and characterized a human NF1‐MPNST explant grown subcutaneously in NOD‐SCID mice, to evaluate the effect of the mTOR inhibitor rapamycin. We demonstrate that rapamycin significantly inhibited human NF1‐MPNST mTOR pathway activation and explant growth in vivo at doses as low as 1.0 mg/kg/day, without systemic toxicities. While rapamycin was effective at reducing NF1‐MPNST proliferation and angiogenesis, with decreased CyclinD1 and VEGF respectively, there was no increase in tumor apoptosis. Rapamycin effectively decreased activation of S6 downstream of mTOR, but there was accompanied increased Akt activation. This study demonstrates the therapeutic potential and limitations of rapamycin in NF1‐associated, and likely sporadic, MPNSTs.     

Overexpression of Midkine in malignant peripheral nerve sheath tumor cells inhibits apoptosis and increases angiogenic potency

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue tumors arising sporadically although more frequently in patients with Neurofibromatosis type 1. Prognosis remains dismal as chemo- and radiotherapy have not been shown to be successful. The heparin-binding growth factor, Midkine (MK), is implicated in the tumorigenesis of benign and plexiform neurofibromas, and thereof arising MPNSTs. MK is mitogenic, anti-apoptotic, angiogenic and can promote tumorigenicity in several cell types. Thus, we investigated the role of MK in malignant biology and tumorigenicity in MPNSTs by stable transfection into MPNST cell lines. Overexpression of MK in the MPNST cell line, S462, increased cell viability and protected cells from apoptosis under serum deprivation, but did not induce proliferation. In addition, MK-transfected S462 cells were partially protected from vincristine-induced cell death. Conditioned medium of MK-transfected S462 cells was a potent mitogen for human umbilical venous endothelial cells. Furthermore, MK overexpression in S462 cells was accompanied by higher levels of VEGF mRNA. Yet, stable overexpression of MK in S462 as well as in ST88-14 cells was not sufficient to promote xenograft tumor growth in nude mice. However, increasing survival and enhanced angiogenic potency of MK-transfected S462 cells highlight the importance of developing specific inhibitors for MK as part of new therapeutic concepts against MPNSTs.     

Poly (ADP) ribose polymerase inhibition: A potential treatment of malignant peripheral nerve sheath tumor

Poly (ADP) ribose polymerase (PARP) inhibitors, first evaluated nearly a decade ago, are primarily used in malignancies with known defects in DNA repair genes, such as alterations in breast cancer, early onset 1/2 (BRCA1/2). While no specific mutations in BRCA1/2 have been reported in malignant peripheral nerve sheath tumors (MPNSTs), MPNST cells could be effectively targeted with a PARP inhibitor to drive cells to synthetic lethality due to their complex karyotype and high level of inherent genomic instability. In this study, we assessed the expression levels of PARP1 and PARP2 in MPNST patient tumor samples and correlated these findings with overall survival. We also determined the level of PARP activity in MPNST cell lines. In addition, we evaluated the efficacy of the PARP inhibitor AZD2281 (Olaparib) in MPNST cell lines. We observed decreased MPNST cell proliferation and enhanced apoptosis in vitro at doses similar to, or less than, the doses used in cell lines with established defective DNA repair genes. Furthermore, AZD2281 significantly reduced local growth of MPNST xenografts, decreased the development of macroscopic lung metastases, and increased survival of mice with metastatic disease. Our results suggest that AZD2281 could be an effective therapeutic option in MPNST and should be further investigated for its potential clinical use in this malignancy.     

Utilization of long-chain free fatty acids and glucose by human leukemic blast cells.

We have studied the utilization of free fatty acid and glucose by human leukemic blast cells. Palmitate was both incorporated into complex cellular lipids, primarily phospholipids and triglycerides, and oxidized to CO2. The predominant phospholipid synthesized was phosphatidylcholine. Only a small proportion of the incoming fatty acid was modified structurally before incorporation into lipid esters. After incubation with [1-14 C]palmitate, 91% of the radioactivity recovered in cell lipids remained in fatty acids containing 16 carbon atoms. Studies with labeled glucose revealed little de novo synthesis of fatty acid, and the majority of the radioactivity from glucose was located in the water-soluble fraction after saponification of the esters. We conclude that the free fatty acids contained in the extracellular fluid provide much of the fatty acid for required cellular lipid synthesis in human leukemic blast cells. Since there is little elongation of incoming palmitate before incorporation into cellular lipids, it may be possible to alter the fatty acid composition of membrane phospholipids by changing the proportion of the various free fatty acids available to the leukemic cells.     

ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer

Enhanced glucose and lipid metabolism is one of the most common properties of malignant cells. ATP citrate lyase (ACLY) is a key enzyme of de novo fatty acid synthesis responsible for generating cytosolic acetyl-CoA and oxaloacetate. To evaluate its role in lung cancer progression, we here analyzed ACLY expression in a subset of human lung adenocarcinoma cell lines and showed a relationship with the phosphatidyl-inositol-3 kinase-Akt pathway. The introduction of constitutively active Akt into cells enhanced the phosphorylation of ACLY, whereas dominant-negative Akt caused attenuation. In human lung adenocarcinoma samples, ACLY activity was found to be significantly higher than in normal lung tissue. Immunohistochemical analysis further showed phosphorylated ACLY overexpression in 162 tumors, well-correlating with stage, differentiation grade, and a poorer prognosis. Finally, to show the therapeutic potential and mechanism of ACLY inhibition for lung cancer treatment, we assessed the effect of RNA interference targeting ACLY on lipogenesis and cell proliferation in A549 cells. ACLY inhibition resulted in growth arrest in vitro and in vivo. Interestingly, increased intracellular lipids were found in ACLY knockdown cells, whereas de novo lipogenesis was inhibited. Supplementation of insulin could rescue the proliferative arrest elicited by ACLY inhibition; however, in contrast, fatty acid palmitate induced cell death. Taken together, these findings suggest that ACLY is involved in lung cancer pathogenesis associated with metabolic abnormality and might offer a novel therapeutic target.     

肿瘤异常脂肪酸代谢研究进展*

肿瘤细胞具有不同于正常细胞的生物学性状和能量代谢机制。最初发现的肿瘤细胞特殊代谢表型称为Warburg效应，后来研究发现恶性肿瘤生长增殖所需的脂肪酸主要来源于从头合成途径，且脂肪酸合成和氧化代谢相关的重要酶类在肿瘤组织中过度表达而在正常组织中不表达或低表达。异常脂肪酸代谢与肿瘤生长、存活及侵袭相关，表明异常脂肪酸代谢为肿瘤生长提供了至关重要的物质和能量来源。近年来，肿瘤细胞异常脂肪酸代谢特异性表型逐渐引起人们高度重视，探索异常脂肪酸代谢在肿瘤生物学中的作用，以及通过靶向脂肪酸代谢途径治疗恶性肿瘤的策略正备受关注。本文就异常脂肪酸代谢对肿瘤形成、发展的意义及特异性抑制剂研发进展作一综述。      

MicroRNA-204 critically regulates carcinogenesis in malignant peripheral nerve sheath tumors

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas accounting for 3%-10% of all soft tissue sarcomas. Neurofibromatosis type 1 (NF1) is the most important known risk factor. MPNSTs are often diagnosed at an advanced stage when distant metastases have developed. Although surgical resection remains the main treatment for MPNSTs, complete surgical resection is rarely possible. The prognosis for patients with MPNSTs is poor. There is an urgent need for improved therapies. To this end, we investigated whether microRNA (miR), specifically miR-204, might be implicated in MPNSTs because it is located at a cancer-associated genomic region exhibiting high frequency of loss of heterozygosity in tumors. We show that miR-204 expression is downregulated in NF1 and non-NF1 MPNST tumor tissues and in tumor cell lines. Restoring miR-204 expression in MPNST cell lines STS26T (non-NF1), ST88-14 (NF1), and T265p21 (NF1) significantly reduces cellular proliferation, migration, and invasion in vitro. Restoring miR-204 expression in STS26T decreases tumor growth and malignant progression in vivo. We also report that miR-204 inhibits Ras signaling and expression of high mobility group gene A2. These findings support the hypothesis that miR-204 plays critical roles in MPNST development and tumor progression. miR-204 may represent a novel biomarker for diagnosis and a candidate target with which to develop effective therapies for MPNSTs.     

脂肪酸从头合成代谢重编程与肿瘤的发生发展

肿瘤细胞代谢重编程是肿瘤发生发展过程中最显著的特征之一,是对肿瘤有氧糖酵解（即Warburg效应）内涵的进一步扩展。细胞癌变过程的代谢模式发生显著变化,涉及到糖酵解、氧化磷酸化、氨基酸代谢、脂肪酸代谢和核酸代谢等诸多方面,其中脂肪酸代谢在肿瘤细胞的能量存储、细胞增殖及重要信号分子合成等方面起到重要作用。研究脂肪酸从头合成代谢的机制与肿瘤发生发展的关系,利用、干预和修正代谢通路上关键酶的异常,正成为肿瘤诊断、预防和治疗的新思路。本文就脂肪酸从头合成代谢重编程与肿瘤发生发展的关系做一综述。      

The pan erbB inhibitor PD168393 enhances lysosomal dysfunction-induced apoptotic death in malignant peripheral nerve sheath tumor cells

Malignant peripheral nerve sheath tumors (MPNSTs) are rapidly progressive Schwann cell neoplasms. The erbB family of membrane tyrosine kinases has been implicated in MPNST mitogenesis and invasion and, thus, is a potential therapeutic target. However, tyrosine kinase inhibitors (TKIs) used alone have limited tumoricidal activity. Manipulating the autophagy lysosomal pathway in cells treated with cytostatic agents can promote apoptotic cell death in some cases. The goal of this study was to establish a mechanistic basis for formulating drug combinations to effectively trigger death in MPNST cells. We assessed the effects of the pan erbB inhibitor PD168393 on MPNST cell survival, caspase activation, and autophagy. PD168393 induced a cytostatic but not a cytotoxic response in MPNST cells that was accompanied by suppression of Akt and mTOR activation and increased autophagic activity. The effects of autophagy modulation on MPNST survival were then assessed following the induction of chloroquine (CQ)-induced lysosomal stress. In CQ-treated cells, suppression of autophagy was accompanied by increased caspase activation. In contrast, increased autophagy induction by inhibition of mTOR did not trigger cytotoxicity, possibly because of Akt activation. We thus hypothesized that dual targeting of mTOR and Akt by PD168393 would significantly increase cytotoxicity in cells exposed to lysosomal stress. We found that PD168393 and CQ in combination significantly increased cytotoxicity. We conclude that combinatorial therapies with erbB inhibitors and agents inducing lysosomal dysfunction may be an effective means of treating MPNSTs.     

Co-targeting the MAPK and PI3K/AKT/mTOR pathways in two genetically engineered mouse models of schwann cell tumors reduces tumor grade and multiplicity

Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that occur spontaneously, or from benign plexiform neurofibromas, in the context of the genetic disorder Neurofibromatosis Type 1 (NF1). The current standard treatment includes surgical resection, high-dose chemotherapy, and/or radiation. To date, most targeted therapies have failed to demonstrate effectiveness against plexiform neurofibromas and MPNSTs. Recently, several studies suggested that the mTOR and MAPK pathways are involved in the formation and progression of MPNSTs. Everolimus (RAD001) inhibits the mTOR and is currently FDA approved for several types of solid tumors. PD-0325901 (PD-901) inhibits MEK, a component of the MAPK pathway, and is currently in clinical trials. Here, we show in vitro than MPNST cell lines are more sensitive to inhibition of cellular growth by Everolimus and PD-901 than immortalized human Schwann cells. In combination, these drugs synergistically inhibit cell growth and induce apoptosis. In two genetically engineered mouse models of MPNST formation, modeling both sporadic and NF1-associated MPNSTs, Everolimus, or PD-901 treatment alone each transiently reduced tumor burden and size, and extended lifespan. However, prolonged treatment of each single agent resulted in the development of resistance and reactivation of target pathways. Combination therapy using Everolimus and PD-901 had synergistic effects on reducing tumor burden and size, and increased lifespan. Combination therapy allowed persistent and prolonged reduction in signaling through both pathways. These data suggest that co-targeting mTOR and MEK may be effective in patients with sporadic or NF1-associated MPNSTs.     

Treatment of orthotopic malignant peripheral nerve sheath tumors with oncolytic herpes simplex virus

Backgrounds

Malignant peripheral nerve sheath tumors (MPNSTs) are an aggressive and often lethal sarcoma that frequently develops in patients with neurofibromatosis type 1 (NF1). We developed new preclinical MPNST models and tested the efficacy of oncolytic herpes simplex viruses (oHSVs), a promising cancer therapeutic that selectively replicates in and kills cancer cells.

Methods

Mouse NF1⁻ MPNST cell lines and human NF1⁻ MPNST stemlike cells (MSLCs) were implanted into the sciatic nerves of immunocompetent and athymic mice, respectively. Tumor growth was followed by external measurement and sciatic nerve deficit using a hind-limb scoring system. Oncolytic HSV G47Δ as well as “armed” G47Δ expressing platelet factor 4 (PF4) or interleukin (IL)-12 were injected intratumorally into established sciatic nerve tumors.

Results

Mouse MPNST cell lines formed tumors with varying growth kinetics. A single intratumoral injection of G47Δ in sciatic nerve tumors derived from human S462 MSLCs in athymic mice or mouse M2 (37-3-18-4) cells in immunocompetent mice significantly inhibited tumor growth and prolonged survival. Local IL-12 expression significantly improved the efficacy of G47Δ in syngeneic mice, while PF4 expression prolonged survival. Injection of G47Δ directly into the sciatic nerve of athymic mice resulted in only mild symptoms that did not differ from phosphate buffered saline control.

Conclusions

Two new orthotopic MPNST models are described, including in syngeneic mice, expanding the options for preclinical testing. Oncolytic HSV G47Δ exhibited robust efficacy in both immunodeficient and immunocompetent MPNST models while maintaining safety. Interleukin-12 expression improved efficacy. These studies support the clinical translation of G47Δ for patients with MPNST.     

Lipoprotein internalisation induced by oncogenic AMPK activation is essential to maintain glioblastoma cell growth

Aim of the studyMetabolic adaptations are essential during tumour growth to maintain the high proliferation levels exhibited by cancer cells. In this study, we examined the transformations that occurred in the lipid metabolism in astrocytic tumours, and the possible role of the fuel-sensing enzyme AMPK. Metabolic targets might help design new and effective drugs for cancer.MethodsTo accomplish this objective, we studied both mice and human astrocytic tumours. We first used a mouse model of astrocytoma driven by oncogenic H-RasV¹² and/or with PTEN deletion based on the common constitutive activation of the Raf/MEK/ERK and PI3K/AKT cascades in human astrocytomas. We then confirmed the results in human glioblastoma cell lines and in glioblastoma tissue samples from patients.ResultsWe show that the high levels of activated AMPK, observed in astrocytic tumours, increase extracellular lipid internalisation and reduce energy expenditure by inhibiting ‘de novo’ fatty acid (FA) synthesis, which allows tumour cells to obtain building blocks and energy to be able to create new organelles and new cells.ConclusionsOur findings demonstrate that AMPK plays a crucial role in glioblastoma cell growth and suggest that blocking lipoprotein receptors could potentially be used as a plausible therapeutic approach for these and other type of tumours with high levels of AMPK.     

肾癌发生发展及转移中脂肪代谢的最新研究进展

肾癌的发病率正在不断上升，透明细胞癌(CCRCC)是其最常见的病理类型，在此类癌的细胞质内可以观察到大量脂类聚集，肾癌细胞会改变其代谢脂质的能力，以支持肿瘤细胞增殖。在肾癌细胞中，许多脂质代谢的关键因子会发生改变，HIF能通过控制脂肪酸代谢来促进CCRCC脂质沉积，在RCC中SREBP1、FAS、ACLY过表达，FAS、ACC的抑制剂能够抑制肾肿瘤细胞的生长，SCD1抑制剂与mTOR抑制剂联合应用可能增强对肾肿瘤细胞的抑制作用，HADHA通过多种代谢途径导致胞质LDs下降，但仍然需要更多关于肾癌脂质代谢的研究，以获得新的治疗肾癌的分子靶点。     

Autophagy mediated lipid catabolism facilitates glioma progression to overcome bioenergetic crisis

Background Activation of mTORC1 plays a significant role in cancer development and progression. However, the metabolic mechanisms to sustain mTORC1 activation of cancer cells within stressed environments are still under-appreciated. We recently revealed high autophagy activity in tumour cells with mTORC1 hyper-activation. Nevertheless, the functions and mechanisms of autophagy in regulating mTORC1 in glioma are not studied.Methods Using glioma patient database and human glioma cells, we assessed the mechanisms and function of selective autophagy to sustain mTORC1 hyper-activation in glioma.Results We revealed a strong association of altered mRNA levels in mTORC1 upstream and downstream genes with prognosis of glioma patients. Our results indicated that autophagy-mediated lipid catabolism was essential to sustain mTORC1 activity in glioma cells under energy stresses. We found that autophagy inhibitors or fatty acid oxidation (FAO) inhibitors in combination with 2-Deoxy-D-glucose (2DG) decreased energy production and survival of glioma cells in vitro. Consistently, inhibition of autophagy or FAO inhibitors with 2DG effectively suppressed the progression of xenografted glioma with hyper-activated mTORC1.Conclusions This study established an autophagy/lipid degradation/FAO/ATP generation pathway, which might be used in brain cancer cells under energy stresses to maintain high mTORC1 signalling for tumour progression.Subject terms: CNS cancer, Autophagy, Molecular biology