Multifaceted Aspects of Metabolic Plasticity in Human Cholangiocarcinoma: An Overview of Current Perspectives
Abstract
1. Introduction
2. Glucose Metabolism and CCA
3. Lipid Metabolism in CCA
4. Protein Metabolism and CCA
5. CCA and Iron
6. Molecular Aspects Underlying CCA Metabolism
6.1. PI3K-AKT-mTOR Signaling Pathway
6.2. SIRT2/cMYC Signaling Pathway
6.3. Uncoupling Protein 2 (UCP2)
6.4. Transcription Factor FOXO1
6.5. Nuclear Receptors: Farnesoid X Receptor (FXR) and Peroxisome Proliferator Activated Receptor-α (PPAR-α)
6.6. Isocitrate Dehidrogenase (IDH)
6.7. Tumor Suppressor p53
6.8. Hif-1α Signaling Pathway
7. Future Directions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
References
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Metabolic Pathways | Metabolic Target | Effects on Cholangiocarcinoma (CCA) | Reference |
---|---|---|---|
Glucose metabolism | GLUT-1 upregulation | Correlation with in vitro CCA cell invasion. Correlation with larger tumor size, poor differentiation, metastasis and poor prognosis of CCA. | [33,34,35] |
PPP upstimulation | Sustainment of both the antioxidant capacity of CCA cells and cisplatin resistance. | [36] | |
PDK overexpression | High serum PDK3 levels correlate with short survival of patients with CCA. PDK1 expression promotes glycolysis and CCA cell proliferation. | [37] | |
SIRT3 effects mediated by HIF1α/ PDK1/PDHA1 pathway | Decrease of SIRT3 expression induced the glycolytic flux through the hypoxia inducible factor α (HIF1α)/PDK1/ PDHA1 axis, promoting CCA progression. | [38] | |
Deregulation of PI3K-AKT-mTOR signaling | Protein overexpression and activation of PI3K have been associated with tumor progression, differentiation, nodal involvement and reduced OS. Upregulation of activated form of AKT have been reported in neoplastic cells compared to the surrounding normal tissue; Increased mTOR gene copy number and elevated phospho-mTOR levels have been described in biliary cancer specimens in comparison to the adjacent normal or dysplastic epithelium. PTEN loss has been related to poor tumor differentiation, nodal involvement and shorter survival in CCA. | [39,40,41,42] | |
SIRT2 overexpression | SIRT2 and its downstream target cMYC, were overexpressed both in human CCA cell lines and in 48 CCA samples compared to adjacent tissues, The SIRT2/cMYC pathway is able to reprogram CCA metabolism through inhibition of OXPHOS and activation of SSP to counteract ROS production, thus protecting CCA cells from oxidative stress-induced apoptosis. | [43] | |
UCP2 overexpression | Up-regulation of UCP2 sustains the EMT and cell invasion of CCA cells. | [44] | |
FXR downregulation | Initiation and progression of CCA, and the downregulation of FXR expression could promote cancer development, modulating the energy metabolism of CCA cells. | [45] | |
PPAR-α upregulation | Tumor occurrence and progression in CCA patients with. | [46,47] | |
IDH1 and IDH2 mutations | Increase of glucose uptake and glucose metabolism as well as upregulation of some metabolites in TCA cycle. Upregulation of PFKP. | [48] | |
Mitochondrial metabolism | PGC1α upregulation | Promotion of CCA metastasis both in vitro and in vivo. | [49] |
Sirt1/FOXO1 stimulation | Involvement in autophagy and mitochondrial dysfunction in CCA cells. | [50] | |
Lipid metabolism | FASN down-regulation | In human and mouse iCCA tissues FASN expression was down- regulated respect to non-tumor adjacent tissues. | [51] |
FA transporter (SLC27A1) overexpression | SCL27A1 silencing in CCA cell lines led to a decrease of cells growth. | [52] | |
FA transporter (FABP5) over expression | Correlation with worse prognosis in eCCA. | [53] | |
COX-2 upregulation | Promotion of CCA growth and invasion. | [54,55,56,57,58] | |
Protein metabolism | Glutamine depletion | Strong depletion: induction a cessation of proliferation or cell death (in vitro addiction to glutamine). Gradual reduction: eCCA cells (EGI-1 and TFK-1) could proliferate under long-term glutamine withdrawal overcoming their addiction to glutamine. | [59] |
ASS deficiency | Reduction of arginine in the surrounding tumor cells could lead to a reduction in CCA cell proliferation. | [60] | |
LAT1 overexpression | Activation of mTOR pathway thus affecting cell proliferation and viability. | [61,62,63] | |
Iron Metabolism | TfR1 high expression | Contribution to CCA progression and poorer clinical outcomes. | [64] |
Ferritin high expression | Negative prognostic index for CCA patients. | [65] | |
Fpn reduced mRNA levels | Reduction of iron release, in tumor cells of CCA patients sample compared to matched surrounding liver, suggests that elevated iron content is a negative prognostic factor. | [65] |
Target | Glucose Metabolism | Reference |
---|---|---|
mTOR | Everolimus | [104,105,106,107] |
Sirolimus | [108,109] | |
Everolimus + CisGem | [110] | |
PI3K | LY294002 | [111] |
Buparlisib | [112] | |
PI-103 | [113] | |
Buparlisib + mFOLFOX6 | [114] | |
Copanlisib ± GemorCisGem | [115] | |
AKT | MK2206 | [116] |
IDH1 | AG-120 | [117] |
AG-221 | [118] | |
AGI-5198 | [48] | |
Lipid Metabolism | ||
SPHK2 | ABC294640 | [100,101,102,103] |
HMGCR | Simvastatin, Atorvastatin | [119] |
Protein Metabolism | ||
LAT1 | 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid | [62] |
JPH203 | [63] | |
ASS | ADI-PEG 20 | [120,121] |
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Pastore, M.; Lori, G.; Gentilini, A.; Taddei, M.L.; Di Maira, G.; Campani, C.; Recalcati, S.; Invernizzi, P.; Marra, F.; Raggi, C. Multifaceted Aspects of Metabolic Plasticity in Human Cholangiocarcinoma: An Overview of Current Perspectives. Cells 2020, 9, 596. https://doi.org/10.3390/cells9030596
Pastore M, Lori G, Gentilini A, Taddei ML, Di Maira G, Campani C, Recalcati S, Invernizzi P, Marra F, Raggi C. Multifaceted Aspects of Metabolic Plasticity in Human Cholangiocarcinoma: An Overview of Current Perspectives. Cells. 2020; 9(3):596. https://doi.org/10.3390/cells9030596
Chicago/Turabian StylePastore, Mirella, Giulia Lori, Alessandra Gentilini, Maria Letizia Taddei, Giovanni Di Maira, Claudia Campani, Stefania Recalcati, Pietro Invernizzi, Fabio Marra, and Chiara Raggi. 2020. "Multifaceted Aspects of Metabolic Plasticity in Human Cholangiocarcinoma: An Overview of Current Perspectives" Cells 9, no. 3: 596. https://doi.org/10.3390/cells9030596
APA StylePastore, M., Lori, G., Gentilini, A., Taddei, M. L., Di Maira, G., Campani, C., Recalcati, S., Invernizzi, P., Marra, F., & Raggi, C. (2020). Multifaceted Aspects of Metabolic Plasticity in Human Cholangiocarcinoma: An Overview of Current Perspectives. Cells, 9(3), 596. https://doi.org/10.3390/cells9030596