The molecular mechanisms responsible for the failure of antiangiogenic therapies and how tumors adapt to these therapies are unclear. Here, we applied transcriptomic, proteomic, and metabolomic approaches to preclinical models and provide evidence for tumor adaptation to vascular endothelial growth factor blockade through a metabolic shift toward carbohydrate and lipid metabolism in tumors. During sunitinib or sorafenib treatment, tumor growth was inhibited and tumors were hypoxic and glycolytic. In sharp contrast, treatment withdrawal led to tumor regrowth, angiogenesis restoration, moderate lactate production, and enhanced lipid synthesis. This metabolic shift was associated with a drastic increase in metastatic dissemination. Interestingly, pharmacological lipogenesis inhibition with orlistat or fatty acid synthase downregulation with shRNA inhibited tumor regrowth and metastases after sunitinib treatment withdrawal. Our data shed light on metabolic alterations that result in cancer adaptation to antiangiogenic treatments and identify key molecules involved in lipid metabolism as putative therapeutic targets.
MT4-MMP (MMP-17) is a glycosylphosphatidyl inositol-anchored matrix metalloprotease expressed on the surface of cancer cells that promotes tumor growth and metastasis. In this report, we identify MT4-MMP as an important driver of cancer cell proliferation through CDK4 activation and retinoblastoma protein inactivation. We also determine a functional link between MT4-MMP and the growth factor receptor EGFR. Mechanistic experiments revealed direct association of MT4-MMP and its positive effects on EGFR phosphorylation in response to TGFa and EGF in cancer cells. Notably, the effects of MT4-MMP on proliferation and EGFR activation did not rely on metalloprotease activity. Clinically, MT4-MMP and EGFR expressions were correlated in human triple-negative breast cancer specimens. Altogether, our results identify MT4-MMP as a positive modifier of EGFR outside-in signaling that acts to cooperatively drive cancer cell proliferation. Cancer Res; 74(23); 6758-70. Ó2014 AACR.
Many studies have evidenced the main role of lipids in physiological and also pathological processes such as cancer, diabetes or neurodegenerative diseases. The identification and the in situ localization of specific low-abundant lipid species involved in cancer biology are still challenging for both fundamental studies and lipid marker discovery. In this paper, we report the identification and the localization of specific isobaric minor phospholipids in human breast cancer xenografts by FTICR MALDI imaging supported by histochemistry. These potential candidates can be further confirmed by liquid chromatography coupled with electrospray mass spectrometry (LC-ESI-MS) after extraction from the region of interest defined by MALDI imaging. Finally, this study highlights the importance of characterizing the heterogeneous distribution of low-abundant lipid species, relevant in complex histological samples for biological purposes.
Exposure to high altitude (HA) affects neurotransmitter levels in the adult brain and induces a number of neurologic and behavioral disturbances. The present work was undertaken to investigate the effects of chronic exposure to a moderate hypoxic environment (natural altitude of 3800 m, 12.8% O2 in inspired air) on the development from birth until adulthood of brain monoamine enzymes in rats. The activity of synthesizing (tyrosine and tryptophan hydroxylase) and catabolizing (catechol-O-methyl transferase and monoamine oxidase) enzymes were studied in discrete brain areas (cerebral cortex, cerebellum, mesodiencephalon, hypothalamus, corpus striatum, and pons medulla) and was shown to be selectively affected by HA, depending on the age of the animal and the brain region. In general, enzyme activity was less susceptible to HA during the first week after birth than at later ages, some brain areas such as the hypothalamus showing significant alterations in some enzymes throughout development, and in all enzymes at adulthood. Furthermore, in all brain areas and at all ages, tyrosine and tryptophan hydroxylase were more affected by HA than the catabolizing enzymes, and their activity was increased in some areas (e.g., cerebral cortex and cerebellum) but decreased in other areas (e.g., hypothalamus, mesodiencephalon, corpus striatum). These enzymatic changes and the corresponding alterations in precursor amino acids, particularly tryptophan, seem to be due more to the direct effect of hypoxia on oxygen-dependent enzymes, than to the stress. It appears that an hypoxic environment may provoke both early and long-term alterations in catecholamine and serotonin metabolism, thus neurotransmitter imbalances may explain some of the alterations in neurologic and endocrine development characteristic of the hypoxic animal.
The US FDA approval of broad-spectrum histone deacetylase (HDAC) inhibitors has firmly laid the cancer community to explore HDAC inhibition as a therapeutic approach for cancer treatment. Hitting one HDAC member could yield clinical benefit but this required a complete understanding of the functions of the different HDAC members. Here we explored the consequences of specific HDAC5 inhibition in cancer cells. We demonstrated that HDAC5 inhibition induces an iron-dependent reactive oxygen species (ROS) production, ultimately leading to apoptotic cell death as well as mechanisms of mitochondria quality control (mitophagy and mitobiogenesis). Interestingly, adaptation of HDAC5-depleted cells to oxidative stress passes through reprogramming of metabolic pathways towards glucose and glutamine. Therefore, interference with both glucose and glutamine supply in HDAC5-inhibited cancer cells significantly increases apoptotic cell death and reduces tumour growth in vivo; providing insight into a valuable clinical strategy combining the selective inhibition of HDAC5 with various inhibitors of metabolism as a new therapy to kill cancer cells.
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