Emerging roles of lipid metabolism in cancer metastasis

Luo, Xiangjian; Cheng, Chunxia; Tan, Zhongping; Li, Namei; Tang, Min; Yang, Lifang; Cao, Yang

doi:10.1186/s12943-017-0646-3

Cited by 497 publications

(412 citation statements)

References 109 publications

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“…Currently, the pivotal role of FA metabolism in cancer metastasis has been highlighted [26], and lncRNAs have been demonstrated to regulate FA metabolism via different mechanisms [27]. Therefore, we further examined whether LNMICC was linked to altered FA metabolism in cervical cancer.…”

Section: Lnmicc Activates Fatty Acid Metabolism In Cervical Cancer Cementioning

confidence: 98%

LNMICC Promotes Nodal Metastasis of Cervical Cancer by Reprogramming Fatty Acid Metabolism

et al. 2018

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Running Title: LNMICC promotes lymph node metastasis in cervical cancer.Key words: lymph node metastasis; fatty acid metabolism; long non-coding RNA; cervical cancer. Conflict of Interest:The authors declare no potential conflicts of interest.Research. AbstractCancer spread to lymph nodes (LN) predicts poor survival but underlying mechanisms remain little understood. In this study, we show that overexpression of the long non-coding RNA LNMICC associates with LN metastasis of primary cervical cancer, where it serves as an independent high-risk factor in patient survival. Functional investigations demonstrated that LNMICC promoted LN metastasis by reprogramming fatty acid metabolism, by recruiting the nuclear factor NPM1 to the promoter of the fatty acid binding protein FABP5. We also found that the pro-metastatic effects of LNMICC were directly targeted and suppressed by miR-190. Our results establish a new mechanism of LN metastasis and highlight LNMICC as a candidate prognostic biomarker and therapeutic target in cervical cancer.

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Section: Lnmicc Activates Fatty Acid Metabolism In Cervical Cancer Cementioning

confidence: 98%

LNMICC Promotes Nodal Metastasis of Cervical Cancer by Reprogramming Fatty Acid Metabolism

et al. 2018

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“…However, one of the key pathological manifestations of PE is a restricted invasion of trophoblast cells [6][7][8]. The rapid growth of tumor cells depends on a sustained energy supply, as highlighted by Luo et al's demonstration of the role of lipid metabolism in tumor invasion [9]; the impairment of trophoblasts invasion in PE placenta may thus be consequent on a compromised energy supply. Pertinently, Yan et al reported that fatty acid binding protein (FABP) expression was increased in placentas from women with PE and that silencing FABP decreased trophoblasts proliferation, migration and invasion [10].…”

Section: Introductionmentioning

confidence: 99%

AMPK Hyper-Activation Alters Fatty Acids Metabolism and Impairs Invasiveness of Trophoblasts in Preeclampsia

Yang

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Preeclampsia (PE) has long been assumed to be an ischemic disease of the placenta, although there is limited evidence as to how the ischemia impacts on the placenta. AMP-activated protein kinase (AMPK) is a key regulator of cellular energy metabolism and plays an important role in a variety of ischemic diseases by enhancing energy production. The present study investigated placental metabolism in PE, and the role of AMPK in regulating trophoblast function. Methods: placentas from normal and PE complicated pregnancies were subjected to GC-MS to identify fatty acids (FA) metabolic fingerprints, and total FA oxidation was assessed by malondialdehyde (MDA) measurement. The AMPK-ACC signaling pathway was assessed by q-PCR and Western Blotting. HTR8/SVneo trophoblast cultures were exposed to different oxygenation conditions to establish an in vitro PE cell model; further analysis by GC-MS for metabolite profiling was then undertaken. Trophoblasts invasion was assessed by a matrigel transwell assay in the presence/absence of AMPK expression and after manipulations of AMPK activity, and then further validated by human villi outgrowth experiments. Results: AMPK phosphorylation and MDA production were significantly elevated in placentas from pregnancies complicated by PE. Metabolism of cis double bond FA was inhibited while trans double bond FA metabolism was promoted in PE placentas. HTR8/SVneo cell culture conditions of persistent low oxygenation mimicked the hyper-activation of AMPK and enhanced the FA oxidation that was observed in PE. AMPK activation impaired trophoblast invasion, while AMPK inhibition promoted trophoblast invasion. Conclusion: PE complicated placentas are associated with AMPK hyper-activation and consequent alterations in FA oxidation, which inhibit trophoblast invasion.

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“…This behavior is greatly aided by an enhanced dependence on glutamine metabolism, which facilitates enhanced lipid synthesis (needed for the formation of LEVs) through GLS, glutamate dehydrogenase (GDH), reductive carboxylation of α‐ketoglutarate (α‐KG) through isocitrate dehydrogenase (IDH), citrate lyase and finally FASN as shown in Figure . This paradigm integrates the role of enhanced glutamine metabolism, enhanced lipid synthesis and lipid metabolism in the establishment of organ specific metastases …”

Section: Discussionmentioning

confidence: 99%

NRH:quinone oxidoreductase 2 (NQO2) and glutaminase (GLS) both play a role in large extracellular vesicles (LEV) formation in preclinical LNCaP‐C4‐2B prostate cancer model of progressive metastasis

et al. 2018

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In the course of studies aimed at the role of oxidative stress in the development of metastatic potential in the LNCaP-C4-2B prostate cancer progression model system, we found a relative decrease in the level of expression of the cytoplasmic nicotinamide riboside: quinone oxidoreductase (NQO2) and an increase in the oxidative stress in C4-2B cells compared to that in LNCaP or its derivatives C4 and C4-2. It was also found that C4-2B cells specifically shed large extracellular vesicles (LEVs) suggesting that these LEVs and their cargo could participate in the establishment of the osseous metastases. The level of expression of caveolin-1 increased as the system progresses from LNCaP to C4-2B. Since NQO2 RNA levels were not changed in LNCaP, C4, C4-2, and C4-2B, we tested an altered cellular distribution hypothesis of NQO2 being compartmentalized in the membrane fractions of C4-2B cells which are rich in lipid rafts and caveolae. This was confirmed when the detergent resistant membrane fractions were probed on immunoblots. Moreover, when the LEVs were analyzed for membrane associated caveolin-1 as possible cargo, we noticed that the enzyme NQO2 was also a component of the cargo along with caveolin-1 as seen in double immunofluorescence studies. Molecular modeling studies showed that a caveolin-1 accessible site is present in NQO2. Specific interaction between NQO2 and caveolin-1 was confirmed using deletion constructs of caveolin-1 fused with glutathione S-transferase (GST). Interestingly, whole cell lysate and mitochondrial preparations of LNCaP, C4, C4-2, and C4-2B showed an increasing expression of glutaminase (GLS, kidney type). The extrusion of LEVs appears to be a specific property of the bone metastatic C4-2B cells and this process could be inhibited by a GLS specific inhibitor BPTES, suggesting the critical role of a functioning glutamine metabolism. Our results indicate that a high level of expression of caveolin-1 in C4-2B cells contributes to an interaction between caveolin-1 and NQO2 and to their packaging as cargo in the shed LEVs. These results suggest an important role of membrane associated oxidoreductases in the establishment of osseous metastases in prostate cancer.

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Emerging roles of lipid metabolism in cancer metastasis

Cited by 497 publications

References 109 publications

LNMICC Promotes Nodal Metastasis of Cervical Cancer by Reprogramming Fatty Acid Metabolism

LNMICC Promotes Nodal Metastasis of Cervical Cancer by Reprogramming Fatty Acid Metabolism

AMPK Hyper-Activation Alters Fatty Acids Metabolism and Impairs Invasiveness of Trophoblasts in Preeclampsia

NRH:quinone oxidoreductase 2 (NQO2) and glutaminase (GLS) both play a role in large extracellular vesicles (LEV) formation in preclinical LNCaP‐C4‐2B prostate cancer model of progressive metastasis

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