C24‐Ceramide Drives Gallbladder Cancer Progression Through Directly Targeting Phosphatidylinositol 5‐Phosphate 4‐Kinase Type‐2 Gamma to Facilitate Mammalian Target of Rapamycin Signaling Activation

The wide prevalence of chemoresistance and compromised early diagnosis of gallbladder cancer (GBC) has led to poor patient prognosis, requiring sustained efforts for the identification of effective biomarkers and therapeutic intervention. Ceramides have emerged as intracellular signaling molecules linked to tumorigenesis and therapeutic response in cancers. However, the clinical relevance of ceramides with GBC has not been investigated.

[1]  T. Lam,et al.  A Metallomic Approach to Assess Associations of Serum Metal Levels With Gallstones and Gallbladder Cancer , 2020, Hepatology.

[2]  Yonglong Zhang,et al.  Cholesterol depletion sensitizes gallbladder cancer to cisplatin by impairing DNA damage response , 2019, Cell cycle.

[3]  Y. N. Park,et al.  Eukaryotic translation initiation factor 6 overexpression plays a major role in the translational control of gallbladder cancer , 2019, Journal of Cancer Research and Clinical Oncology.

[4]  T. Pawlik,et al.  Molecular pathways and potential biomarkers in gallbladder cancer: A comprehensive review. , 2019, Surgical oncology.

[5]  S. Conner,et al.  PI5P4Kγ functions in DTX1-mediated Notch signaling , 2018, Proceedings of the National Academy of Sciences.

[6]  D. Rockey,et al.  Nanoliposome C6-Ceramide Increases the Anti-tumor Immune Response and Slows Growth of Liver Tumors in Mice , 2018, Gastroenterology.

[7]  A. Heck,et al.  A search for ceramide binding proteins using bifunctional lipid analogs yields CERT-related protein StarD7[S] , 2018, Journal of Lipid Research.

[8]  B. Ogretmen,et al.  Sphingolipid metabolism in cancer signalling and therapy , 2017, Nature Reviews Cancer.

[9]  Robert Reihs,et al.  IMP2/IGF2BP2 expression, but not IMP1 and IMP3, predicts poor outcome in patients and high tumor growth rate in xenograft models of gallbladder cancer , 2017, Oncotarget.

[10]  A. Jemal,et al.  Limited Use of Adjuvant Therapy in Patients With Resected Gallbladder Cancer Despite a Strong Association With Survival , 2017, Journal of the National Cancer Institute.

[11]  D. Sabatini,et al.  mTOR Signaling in Growth, Metabolism, and Disease , 2017, Cell.

[12]  T. Kitamura,et al.  Ceramide-CD300f Binding Inhibits Lipopolysaccharide-induced Skin Inflammation , 2017, The Journal of Biological Chemistry.

[13]  Yonglong Zhang,et al.  Hippocalcin‐like 1 suppresses hepatocellular carcinoma progression by promoting p21Waf/Cip1 stabilization by activating the ERK1/2‐MAPK pathway , 2016, Hepatology.

[14]  S. Bidlingmaier,et al.  Proteome-wide Identification of Novel Ceramide-binding Proteins by Yeast Surface cDNA Display and Deep Sequencing* , 2016, Molecular & Cellular Proteomics.

[15]  T. Kitamura,et al.  Ceramide-CD300f binding suppresses experimental colitis by inhibiting ATP-mediated mast cell activation , 2015, Gut.

[16]  Deborah A. Sarkes,et al.  PIP4kγ is a substrate for mTORC1 that maintains basal mTORC1 signaling during starvation , 2014, Science Signaling.

[17]  U. Nöthlings,et al.  Inflammatory and metabolic biomarkers and risk of liver and biliary tract cancer , 2014, Hepatology.

[18]  S. Morad,et al.  Ceramide-orchestrated signalling in cancer cells , 2012, Nature Reviews Cancer.

[19]  A. Merrill,et al.  Modulation of Ceramide Synthase Activity via Dimerization* , 2012, The Journal of Biological Chemistry.

[20]  Y. Hannun,et al.  Results of a Phase II Trial of Gemcitabine Plus Doxorubicin in Patients with Recurrent Head and Neck Cancers: Serum C18-Ceramide as a Novel Biomarker for Monitoring Response , 2011, Clinical Cancer Research.

[21]  M. Copur,et al.  Brief commentary: largest randomized trial of biliary tract cancer treatment with cisplatin plus gemcitabine versus gemcitabine alone: an excellent opportunity to evaluate the prognostic value of tumor marker CA 19-9. , 2011, Clinical colorectal cancer.

[22]  G. Gores,et al.  Combination of gemcitabine and cisplatin for biliary tract cancer: a platform to build on. , 2011, Journal of hepatology.

[23]  C. Lepage,et al.  Trends in the incidence and management of biliary tract cancer: a French population-based study. , 2011, Journal of hepatology.

[24]  M. Chung,et al.  Preoperative Serum CA 19-9 Level as a Predictive Factor for Recurrence after Curative Resection in Biliary Tract Cancer , 2011, Annals of Surgical Oncology.

[25]  Zhou Wang,et al.  C6-ceramide synergistically potentiates the anti-tumor effects of histone deacetylase inhibitors via AKT dephosphorylation and α-tubulin hyperacetylation both in vitro and in vivo , 2011, Cell Death and Disease.

[26]  M. Kester,et al.  Nanoliposomal ceramide prevents in vivo growth of hepatocellular carcinoma , 2010, Gut.

[27]  B. Yang,et al.  Exogenous cell-permeable C6 ceramide sensitizes multiple cancer cell lines to Doxorubicin-induced apoptosis by promoting AMPK activation and mTORC1 inhibition , 2010, Oncogene.

[28]  J. Piette,et al.  The proapoptotic C16-ceramide-dependent pathway requires the death-promoting factor Btf in colon adenocarcinoma cells. , 2009, Journal of proteome research.

[29]  H. Ackermann,et al.  Ceramide synthases and ceramide levels are increased in breast cancer tissue. , 2009, Carcinogenesis.

[30]  R. Sears,et al.  Direct interaction between the inhibitor 2 and ceramide via sphingolipid‐protein binding is involved in the regulation of protein phosphatase 2A activity and signaling , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[31]  Yusuf A. Hannun,et al.  Principles of bioactive lipid signalling: lessons from sphingolipids , 2008, Nature Reviews Molecular Cell Biology.

[32]  Y. Hannun,et al.  Clinical relevance of ceramide metabolism in the pathogenesis of human head and neck squamous cell carcinoma (HNSCC): attenuation of C(18)-ceramide in HNSCC tumors correlates with lymphovascular invasion and nodal metastasis. , 2007, Cancer letters.

[33]  S. Ben-Dor,et al.  When Do Lasses (Longevity Assurance Genes) Become CerS (Ceramide Synthases)? , 2006, Journal of Biological Chemistry.

[34]  E. Tran,et al.  Direct Binding to Ceramide Activates Protein Kinase Cζ before the Formation of a Pro-apoptotic Complex with PAR-4 in Differentiating Stem Cells*[boxs] , 2005, Journal of Biological Chemistry.

[35]  V. Briner,et al.  Differential binding of ceramide to MEKK1 in glomerular endothelial and mesangial cells. , 2004, Biochimica et biophysica acta.

[36]  H. Riezman,et al.  Upstream of Growth and Differentiation Factor 1 (uog1), a Mammalian Homolog of the Yeast Longevity Assurance Gene 1 (LAG1), RegulatesN-Stearoyl-sphinganine (C18-(Dihydro)ceramide) Synthesis in a Fumonisin B1-independent Manner in Mammalian Cells* , 2002, The Journal of Biological Chemistry.

[37]  W. Schneider-Brachert,et al.  Cathepsin D targeted by acid sphingomyelinase‐derived ceramide , 1999, The EMBO journal.

[38]  M. Czaja,et al.  Ceramide induces caspase‐independent apoptosis in rat hepatocytes sensitized by inhibition of RNA synthesis , 1999, Hepatology.

[39]  J. Pfeilschifter,et al.  Ceramide-binding and activation defines protein kinase c-Raf as a ceramide-activated protein kinase. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[40]  W. J. Dyer,et al.  A rapid method of total lipid extraction and purification. , 1959, Canadian journal of biochemistry and physiology.

[41]  A. Futerman,et al.  Increased ceramide synthase 2 and 6 mRNA levels in breast cancer tissues and correlation with sphingosine kinase expression. , 2010, Biochemical and biophysical research communications.