Acid Sphingomyelinase Downregulation Enhances Mitochondrial Fusion and Promotes Oxidative Metabolism in a Mouse Model of Melanoma

Melanoma is the most severe type of skin cancer. Its unique and heterogeneous metabolism, relying on both glycolysis and oxidative phosphorylation, allows it to adapt to disparate conditions. Mitochondrial function is strictly interconnected with mitochondrial dynamics and both are fundamental in tumour progression and metastasis. The malignant phenotype of melanoma is also regulated by the expression levels of the enzyme acid sphingomyelinase (A-SMase). By modulating at transcriptional level A-SMase in the melanoma cell line B16-F1 cells, we assessed the effect of enzyme downregulation on mitochondrial dynamics and function. Our results demonstrate that A-SMase influences mitochondrial morphology by affecting the expression of mitofusin 1 and OPA1. The enhanced expression of the two mitochondrial fusion proteins, observed when A-SMase is expressed at low levels, correlates with the increase of mitochondrial function via the stimulation of the genes PGC-1alpha and TFAM, two genes that preside over mitochondrial biogenesis. Thus, the reduction of A-SMase expression, observed in malignant melanomas, may determine their metastatic behaviour through the stimulation of mitochondrial fusion, activity and biogenesis, conferring a metabolic advantage to melanoma cells.

[1]  Lei Jiang,et al.  Dysregulated Mitochondrial Dynamics and Metabolism in Obesity, Diabetes, and Cancer , 2019, Front. Endocrinol..

[2]  E. Clementi,et al.  XIAP as a Target of New Small Organic Natural Molecules Inducing Human Cancer Cell Death , 2019, Cancers.

[3]  S. Castiglioni,et al.  3D Quantitative and Ultrastructural Analysis of Mitochondria in a Model of Doxorubicin Sensitive and Resistant Human Colon Carcinoma Cells , 2019, Cancers.

[4]  M. R. Ruocco,et al.  Metabolic flexibility in melanoma: a potential therapeutic target. , 2019, Seminars in cancer biology.

[5]  M. Pistello,et al.  Sphingolipid/Ceramide Pathways and Autophagy in the Onset and Progression of Melanoma: Novel Therapeutic Targets and Opportunities , 2019, International journal of molecular sciences.

[6]  E. Clementi,et al.  The Natural Compound Climacostol as a Prodrug Strategy Based on pH Activation for Efficient Delivery of Cytotoxic Small Agents , 2019, Front. Chem..

[7]  V. Calvo,et al.  Cisplatin resistance involves a metabolic reprogramming through ROS and PGC‐1&agr; in NSCLC which can be overcome by OXPHOS inhibition , 2019, Free radical biology & medicine.

[8]  A. Daher,et al.  Sphingomyelin Synthase 1 (SMS1) Downregulation Is Associated With Sphingolipid Reprogramming and a Worse Prognosis in Melanoma , 2019, Front. Pharmacol..

[9]  E. Clementi,et al.  The Fine Tuning of Drp1-Dependent Mitochondrial Remodeling and Autophagy Controls Neuronal Differentiation , 2019, Front. Cell. Neurosci..

[10]  F. Bost,et al.  The metabolic modulator PGC-1α in cancer. , 2019, American Journal of Cancer Research.

[11]  S. Majumdar,et al.  TNFα mediated ceramide generation triggers cisplatin induced apoptosis in B16F10 melanoma in a PKCδ independent manner , 2018, Oncotarget.

[12]  J. Wayne,et al.  Follow‐up of the melanoma patient , 2018, Journal of surgical oncology.

[13]  J. Marine,et al.  Targeting the Sphingosine 1-Phosphate Axis Exerts Potent Antitumor Activity in BRAFi-Resistant Melanomas , 2018, Molecular Cancer Therapeutics.

[14]  J. R. Plaça,et al.  Mitochondrial transcription factor A (TFAM) shapes metabolic and invasion gene signatures in melanoma , 2018, Scientific Reports.

[15]  E. Clementi,et al.  Autophagy controls neonatal myogenesis by regulating the GH-IGF1 system through a NFE2L2- and DDIT3-mediated mechanism , 2018, Autophagy.

[16]  Sun-Hee Kim,et al.  Mitochondrial dynamic alterations regulate melanoma cell progression , 2018, Journal of cellular biochemistry.

[17]  Min Zhou,et al.  Dynamin‐related protein 1‐mediated mitochondrial fission contributes to IR‐783‐induced apoptosis in human breast cancer cells , 2018, Journal of cellular and molecular medicine.

[18]  G. Lucignani,et al.  Nitric Oxide Generated by Tumor-Associated Macrophages Is Responsible for Cancer Resistance to Cisplatin and Correlated With Syntaxin 4 and Acid Sphingomyelinase Inhibition , 2018, Front. Immunol..

[19]  I. Eberini,et al.  Design, synthesis, molecular modelling and in vitro cytotoxicity analysis of novel carbamate derivatives as inhibitors of Monoacylglycerol lipase. , 2018, Bioorganic & medicinal chemistry.

[20]  H. Levine,et al.  Elucidating the Metabolic Plasticity of Cancer: Mitochondrial Reprogramming and Hybrid Metabolic States , 2018, Cells.

[21]  R. Deberardinis,et al.  Metabolic strategies of melanoma cells: Mechanisms, interactions with the tumor microenvironment, and therapeutic implications , 2018, Pigment cell & melanoma research.

[22]  E. Catalani,et al.  Autophagy‐mediated neuroprotection induced by octreotide in an ex vivo model of early diabetic retinopathy , 2017, Pharmacological research.

[23]  H. Rezvani,et al.  Energy metabolism in skin cancers: A therapeutic perspective. , 2017, Biochimica et biophysica acta. Bioenergetics.

[24]  M. Dany Sphingosine metabolism as a therapeutic target in cutaneous melanoma. , 2017, Translational research : the journal of laboratory and clinical medicine.

[25]  Jesse D. Gelles,et al.  Disruption of mitochondrial electron transport chain function potentiates the pro-apoptotic effects of MAPK inhibition , 2017, The Journal of Biological Chemistry.

[26]  J. Vachtenheim The Many Roles of MITF in Melanoma , 2017 .

[27]  D. Fisher,et al.  The master role of microphthalmia-associated transcription factor in melanocyte and melanoma biology. , 2017, Laboratory investigation; a journal of technical methods and pathology.

[28]  E. Clementi,et al.  Reversal of Defective Mitochondrial Biogenesis in Limb-Girdle Muscular Dystrophy 2D by Independent Modulation of Histone and PGC-1α Acetylation. , 2016, Cell reports.

[29]  A. Fausto,et al.  Natural products from aquatic eukaryotic microorganisms for cancer therapy: Perspectives on anti-tumour properties of ciliate bioactive molecules. , 2016, Pharmacological research.

[30]  E. Clementi,et al.  Climacostol reduces tumour progression in a mouse model of melanoma via the p53-dependent intrinsic apoptotic programme , 2016, Scientific Reports.

[31]  G. Mills,et al.  Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors. , 2016, The Journal of clinical investigation.

[32]  M. Herlyn,et al.  Mitochondrial biogenesis meets chemoresistance in BRAF-mutant melanoma , 2016, Molecular & cellular oncology.

[33]  E. Clementi,et al.  Essential role for acid sphingomyelinase-inhibited autophagy in melanoma response to cisplatin , 2016, Oncotarget.

[34]  Z. Ronai,et al.  Regulators of mitochondrial dynamics in cancer. , 2016, Current opinion in cell biology.

[35]  L. Wiemerslage,et al.  Quantification of mitochondrial morphology in neurites of dopaminergic neurons using multiple parameters , 2016, Journal of Neuroscience Methods.

[36]  F. Rumjanek,et al.  Enhanced OXPHOS, glutaminolysis and β-oxidation constitute the metastatic phenotype of melanoma cells. , 2016, The Biochemical journal.

[37]  Prashant Mishra,et al.  Metabolic regulation of mitochondrial dynamics , 2016, The Journal of cell biology.

[38]  A. Ganesan,et al.  Acid Ceramidase in Melanoma , 2015, The Journal of Biological Chemistry.

[39]  E. Clementi,et al.  Modulation of Acid Sphingomyelinase in Melanoma Reprogrammes the Tumour Immune Microenvironment , 2015, Mediators of inflammation.

[40]  K. Schmid,et al.  Regulation of hematogenous tumor metastasis by acid sphingomyelinase , 2015, EMBO molecular medicine.

[41]  B. Han,et al.  Mitofusin-2 over-expresses and leads to dysregulation of cell cycle and cell invasion in lung adenocarcinoma , 2015, Medical Oncology.

[42]  M. Bianchi,et al.  5‐Fluorouracil causes leukocytes attraction in the peritoneal cavity by activating autophagy and HMGB1 release in colon carcinoma cells , 2015, International journal of cancer.

[43]  Xin Sheng Wang,et al.  Warburg Effect or Reverse Warburg Effect? A Review of Cancer Metabolism , 2015, Oncology Research and Treatment.

[44]  E. Clementi,et al.  The emerging role of Acid Sphingomyelinase in autophagy , 2015, Apoptosis.

[45]  J. Chipuk,et al.  Mitochondrial division is requisite to RAS-induced transformation and targeted by oncogenic MAPK pathway inhibitors. , 2015, Molecular cell.

[46]  E. Clementi,et al.  Deficient nitric oxide signalling impairs skeletal muscle growth and performance: involvement of mitochondrial dysregulation , 2014, Skeletal Muscle.

[47]  Kakajan Komurov,et al.  Inhibition of mTORC1/2 overcomes resistance to MAPK pathway inhibitors mediated by PGC1α and oxidative phosphorylation in melanoma. , 2014, Cancer research.

[48]  Giovanna Ambrosini,et al.  The Eukaryotic Promoter Database: expansion of EPDnew and new promoter analysis tools , 2014, Nucleic Acids Res..

[49]  R. Kalluri,et al.  PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation to promote metastasis , 2014, Nature Cell Biology.

[50]  J. Nunnari,et al.  Mitochondrial form and function , 2014, Nature.

[51]  E. Clementi,et al.  Nitric oxide drives embryonic myogenesis in chicken through the upregulation of myogenic differentiation factors. , 2014, Experimental cell research.

[52]  E. Clementi,et al.  Acid sphingomyelinase determines melanoma progression and metastatic behaviour via the microphtalmia-associated transcription factor signalling pathway , 2013, Cell Death and Differentiation.

[53]  S. Archer Mitochondrial dynamics--mitochondrial fission and fusion in human diseases. , 2013, The New England journal of medicine.

[54]  R. Weichselbaum,et al.  Adenoviral Transduction of Human Acid Sphingomyelinase into Neo-Angiogenic Endothelium Radiosensitizes Tumor Cure , 2013, PloS one.

[55]  Alexander M van der Bliek,et al.  Mechanisms of mitochondrial fission and fusion. , 2013, Cold Spring Harbor perspectives in biology.

[56]  Jun S. Song,et al.  Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF. , 2013, Cancer cell.

[57]  P. Puigserver,et al.  PGC1α expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. , 2013, Cancer cell.

[58]  C. Touriol,et al.  The nonlysosomal β‐glucosidase GBA2 promotes endoplasmic reticulum stress and impairs tumorigenicity of human melanoma cells , 2013, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[59]  D. Chan Fusion and fission: interlinked processes critical for mitochondrial health. , 2012, Annual review of genetics.

[60]  J. Kirkwood,et al.  Importance of glycolysis and oxidative phosphorylation in advanced melanoma , 2012, Molecular Cancer.

[61]  J. Kirkwood,et al.  Mitochondrial Respiration - An Important Therapeutic Target in Melanoma , 2012, PloS one.

[62]  L. Obeid,et al.  Ceramide and apoptosis: exploring the enigmatic connections between sphingolipid metabolism and programmed cell death. , 2012, Anti-cancer agents in medicinal chemistry.

[63]  Andrei L Osterman,et al.  Comparative Metabolic Flux Profiling of Melanoma Cell Lines , 2011, The Journal of Biological Chemistry.

[64]  E. Clementi,et al.  Syntaxin 4 Is Required for Acid Sphingomyelinase Activity and Apoptotic Function* , 2010, The Journal of Biological Chemistry.

[65]  J. Martinou,et al.  Mitochondrial dynamics and cancer. , 2009, Seminars in cancer biology.

[66]  E. Schuchman,et al.  Acid sphingomyelinase overexpression enhances the antineoplastic effects of irradiation in vitro and in vivo. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[67]  E. Clementi,et al.  Nitric oxide boosts chemoimmunotherapy via inhibition of acid sphingomyelinase in a mouse model of melanoma. , 2007, Cancer research.

[68]  R. Youle,et al.  Mitochondrial fission in apoptosis , 2005, Nature Reviews Molecular Cell Biology.

[69]  Limin Liu,et al.  Screening for Nitric Oxide-Dependent Protein-Protein Interactions , 2003, Science.

[70]  E. Gulbins,et al.  Melanoma cell metastasis via P-selectin-mediated activation of acid sphingomyelinase in platelets , 2016, Clinical & Experimental Metastasis.

[71]  T. Levade,et al.  Dysregulation of Sphingolipid Metabolism in Melanoma: Roles in Pigmentation, Cell Survival and Tumor Progression , 2015 .

[72]  Chen Liu,et al.  OPA1 downregulation is involved in sorafenib-induced apoptosis in hepatocellular carcinoma , 2013, Laboratory Investigation.

[73]  V. Madeira Overview of mitochondrial bioenergetics. , 2012, Methods in molecular biology.