Understanding and Targeting Apoptotic Pathways in Ovarian Cancer
Abstract
:1. Introduction
1.1. Historical View of Cell Death
1.2. Apoptosis
1.2.1. Intrinsic Apoptotic Pathway
1.2.2. Extrinsic Apoptotic Pathway
2. Apoptotic Mechanisms Altered in OvCa
2.1. Activators of Apoptosis in OvCa
2.2. Inhibitors of Apoptosis Proteins (IAP) in OvCa
2.3. Ubiquitination Mediated Apoptosis in OvCa
3. Regulation of OvCa Apoptosis via Glycosylation and Glycan-Related Proteins
3.1. O-Linked Glycosylation
3.2. N-Linked Glycosylation
4. Apoptosis Regulation by Galectins
5. Epigenetic Modifications and Their Role in OvCa Apoptosis
5.1. miRNAs in OvCa Apoptosis
5.2. DNA Methylation
5.3. Histone Acetylation
6. Clinical Use of Drugs Targeting Apoptosis in Ovarian Cancer
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
AMPK | 5′ AMP-activated protein kinase |
CA125 | Cancer antigen 125, mucin 16 |
CA-MSCs | Cancer-associated mesenchymal cells |
CDT2 | Cell division cycle protein 2 |
CRL | Cullin-RING ubiquitin ligases |
CRL4 | Cullin-really interesting new gene ubiquitin ligase 4 |
DcR3 | Decoy Receptor 3 |
DDB2 | Damage Specific DNA Binding Protein 2 |
DISC | Death-inducing signal complex |
DNMT | DNA methyltransferase |
EF24 | 3,5-bis(2-flurobenzylidene) piperidin-4-one |
FADD | Fas-associated death domain protein |
FLIP | IL-1 β-converting enzyme (FLICE)-like inhibitory proteins (FLIP) |
FasL | Fas ligand |
FDA | Food and drug administration |
FLICE | Fas-associated death domain-like interleukin-1β-converting enzyme |
FLIP | FLICE-like inhibitory protein |
FITC | Fluorescein isothiocyanate |
GLUT1 | Glucose transporter 1 |
hOSE | Human ovarian surface epithelium |
IAP | Inhibitor of apoptosis |
KGDH | α-Ketoglutarate dehydrogenase |
MAPK | Mitogen-activated protein kinase |
miRNA | Small non-coding RNA |
MTT | 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide |
mTOR | Mammalian target of rapamycin |
NAD | Nicotinamide adenine dinucleotide |
NAE | NEDD8-activating Enzyme E1 |
NF-κB | Nuclear factor κB |
O-GlcNAc | O-linked N-acetylglucosamine |
OvCa | Ovarian cancer |
PARP | Poly-ADP ribose polymerase |
PDK1 | Pyruvate dehydrogenase kinase 1 |
PI | Propidium iodide |
PTEN | Phosphatase and tensin homolog |
ROC1 | Regulator of Cullins-1 |
ROS | Reactive oxygen species |
SCF | CRL/Skp Cullin F-box containing complex |
scFvs | Single chain variable fragments |
shRNA | Short hairpin RNA |
SM | Smac-mimetics |
SNA | Sambucus nigra agglutinin |
ST6Gal1 | Sialyltransferase β-galactosamide α-2, 6-sialyltransterase 1 |
TCA | Tricarboxylic acid |
TLR4 | Toll-Like Receptor 4 |
TNF | Tumor necrosis factor |
TRAIL | TNF-related apoptosis-inducing ligand |
TUNEL | Terminal deoxynucleotidyl transferase dUTP nick end labeling |
UPS | Ubiquitin-proteasome-system |
UPS14 | Ubiquitin-specific protease 14 |
VPRBP | Viral protein R binding protein |
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microRNA (miRNA) | Function | Methods Used | Citation |
---|---|---|---|
miRNA-15a | Bmi-1 is elevated in OvCa cells and tissue samples There is an inverse correlation between miRNA15a and Bmi-1 over expressing miRNA-15a down regulates Bmi-1 protein in OvCa reducing cell proliferation | qPCR, western blot analysis, reporter assay | Bhattacharya et al., 2009 [89] |
miRNA-16 | miRNA-16 down regulates Bmi-1 (Battacharya, 2009) and Bcl-2 (Cimmino, 2005) protein expression | Western blot analysis, TUNEL | Bhattacharya et al., 2009 [89], Cimmino et al., 2005 [90] |
miRNA-18a | Overexpression of miRNA-18a in OvCa cell lines decreases levels of TRIAP1, IPMK, and cleaved Caspase 3 and increases apoptosis in vivo | Western blot analysis, TUNEL | Liu et al., 2017 [91] |
miRNA-21 | Inhibition of miRNA 21 resulted in reduced pAKT and upregulated PTEN (Liu, 2019) and c-IAP2 (Chan, 2014) which interferes, with caspase activation in human OvCa cell lines. | Reporter assay, western blot analysis, qPCR, Annexin V | Chan et al., 2014 [82], Lou et al., 2011 [86], Liu et al., 2019 [87] |
miRNA-25 | Knockdown of miRNA-25 in OvCa cell lines decreases Bim and Bcl2 levels, increases, Bax, cleaved Caspase-3 levels and apoptosis | Annexin V, western blot analysis | Zhang et al., 2012 [80], Sarkozy et al., 2018 [83] |
miRNA-31 | In p53 deficient OvCa cell lines, miRNA-31 can induce p53-mediated apoptosis indirectly by targeting E2F2, MIR31, and CDKN2A genes. | qPCR, molecular profiling | Creighton et al., 2010 [81] |
miRNA-34 | OvCa cell lines transfected with miRNA-34 mimics increase levels of Bax, while decreasing levels of Bcl-2 leading to increased apoptosis | Annexin V, western blot analysis | Jia et al., 2019 [92] |
miRNA-93-5P | Overexpression of miRNA-93-5P in OvCa cell lines decreases levels of Bcl/xl, cleaved PARP, and increases levels of p53 and apoptosis. | Annexin V, western blot analysis | Chen et al., 2015 [93] |
miRNA-106a | Inhibition of miR-106a enhanced the sensitivity of the OvCa cells to chemotherapy and increased apoptosis. Increasing miRNA-106a decreased PDCD4 levels. PDCD4 silencing led to a decrease in cleaved pro-Caspasse-3 and -9. | Flow Cytometry, western blot analysis | Rao et al 2013 [94], Li et al, 2014 [95] |
miRNA-124 | Overexpression levels of miRNA-124 increases apoptosis and decreased levels of PDCD6 in OvCa cell lines | Annexin V, qPCR | Yuan et al., 2017 [96] |
miRNA-130a | miRNA-130a downregulates XIAP in human A2780 cells. | qPCR, western blot analysis, flow cytometric analysis, reporter assay, Annexin V | Zhang et al., 2013 [97] |
miRNA-135a | Transfection with an miRNA-135a mimic increases Caspase-3 activity and p53 levels and decreases Bcl-2 levels in OvCa cell lines. | Western blot, Caspase-3 activity assay, Annexin V | Tang et al., 2014 [98] |
miRNA-137 | miR-137 knockout by CRISPR/Cas9 increases XIAP levels and inhibits apoptosis in OvCa cell lines | TUNEL, DAPI, western blot analysis | Li et al., 2017 [99] |
miR-142-5p | miRNA-142-5p inhibits XIAP in human OvCa cell lines. miR-142-5p targeted anti-apoptotic genes (Birc3, Bcl2, Bcl2L2 and Mcl1) | Dual luciferase assay, western blot analysis, flow cytometric analysis | Li et al., 2019 [88], Su et al. 2019 [100] |
miR-147b | Elevated miRNA-147b results in increased Bak1 and Bax levels and reduces levels of Bcl-2 and Bcl-xl in SKOV3 cells. | Molecular profiling, western blot analysis, Caspase-3 and 7 activity, mitochondrial potential | Kleemann et al., 2017 [101] |
miRNA-149 | Downregulation of miRNA-149 decreases apoptosis in OvCa cells pre-treated with paclitaxel. Downregulation of miRNA-149 decreases Bax mRNA and protein and increases Bcl-2 mRNA and protein expression inhibits XIAP expression in human OvCa cells. Overexpression of miRNA-149 decreases XIAP mRNA and protein expression and increases apoptosis in OvCa cell lines. | Annexin V, qPCR, western blot analysis | Sun et al., 2018 [102], Zhan et al., 2015 [103] |
miRNA-152 | Overexpression of miRNA-152 decreased DNMT1 and increased apoptosis and in OvCa cell lines. | Annexin V, western blot analysis, qPCR | Xiang et al., 2014 [104] |
miRNA-181a | Overexpression of miRNA-181a decreased apoptosis in OvCa cells | Annexin V | Li et al., 2016 [105] |
miRNA-193a and miR-193b | Overexpression of miRNA-193a or miRNA-193b increases activity of Caspase-3 and -7 in OvCa cells. miRNA-193a also decreases levels of anti-apoptotic factor MCL1 in OvCa cells | Caspase-3 and -7 activity, western blot analysis | Nakano et al., 2013 [106] |
miRNA-195-5p | Overexpression of miRNA-195-5p increases apoptosis in OvCa cells and in a in vivo model. | Annexin V, TUNEL | Dai et al., 2019 [107] |
miRNA-221 | Inhibiting miRNA-221 increases APAF1 and apoptosis in OvCa cells | Annexin V, western blot analysis, Hoechst 33342 staining | Li et al., 2017 [108] |
miRNA-338-3p | miRNA-338-3p induces apoptosis by binding to long non-coding RNA LINC00460. | Luciferase reporter assay, western blot analysis, flow cytometric assay | Liu et al., 2018 [109] |
miRNA-493-3p | Overexpression of miRNA-493-3p in OvCa cell lines increased Bak levels, release of cytochrome C, cleavage of Caspase-3 and PARP and decreased Bcl-XL levels | Western blot analysis, free cytochrome C staining, Annexin V | Kleeman et al., 2019 [110] |
miRNA-614 | Overexpression of miRNA-614 decreases level of Bad and increases apoptosis in OvCa cells. | Annexin V, western blot analysis | Zhang et al., 2018 [111] |
miRNA-630 | Silencing of miRNA-630 in OvCa cell lines increases cleaved Caspase-3, PTEN levels and apoptosis. | Annexin V, western blot analysis | Eoh et al., 2018 [112], Zou et al., 2015 [113] |
miRNA-718 | Overexpression of miRNA-718 in OvCa cell lines decreases VEGF levels and increases apoptosis. This is reversed when VEGF is restored | Annexin V, western blot analysis | Leng et al., 2014 [114] |
miRNA-744-5p | Increased expression of miRNA-744-5p increased levels of cleaved Caspase-3, and PARP and decreased levels of Bcl2 in OvCa cell lines. | AnnexinV, western blot analysis, Caspase-3 and 7 activity, mitochondrial membrane potential | Kleemann et al., 2018 [115] |
miRNA-1284 | Inhibiting miRNA-1284 results in increased Bcl-2 levels and decreased Bax, and cleaved Caspase-3 levels in OvCa cell line. An miRNA-1284 mimic increases apoptosis | Annexin V, western blot analysis | Pan et al., 2016 [116] |
Drug Treatment | Suspected Target Related to Apoptosis | Last Reported Phase | Cancer Type | NCT |
---|---|---|---|---|
Epothilone B | TRAIL and Caspase-8 | Phase II | Recurrent ovarian | NCT00035100 |
Epothilone B versus Doxorubicin | TRAIL and Caspase-8 | Phase III | Ovarian, Primary Fallopian, or Peritoneal Cancer | NCT00262990 |
Epothilone B + Omeprazole + Midalzolam | TRAIL and Caspase-8 | Phase I | Advanced malignancies | NCT00420615 |
Metformin + Paclitaxel + Carboplatin | mTOR pathway circumventing p53-induced | Phase II | Advanced stage ovarian carcinoma | NCT02437812 |
DEBIO 1143+ Carboplatin + Paclitaxel | cIAP1 | Phase II | Epithelial ovarian cancer | NCT01930292, NCT03270176 |
DEBIO 1143+ Avelumab | cIAP1 | Phase I | Advanced solid malignancies | NCT03270176 |
LCL161 | XIAP, cIAP1 and cIAP2 | Phase II | Solid tumors | NCT02649673 |
Birinapant | IAPs, cIAP1 and cIAP2 and activate Caspase-3 | Phase I/II | Solid tumors | NCT01940172 |
ABT 737/ABT 263 (navitoclax) | Bcl-2/Bcl-XL | Ex vivo study | Ovarian tumors | NCT01440504 |
Venclexta (ABT-199) | Bcl-2 inhibitor | Approved | Chronic lymphocytic leukemia | - |
PRIMA-1MET (APR-246) | p53 | Phase II | High-grade serous ovarian cancer, high grade serious ovarian cancer (Platinum-Resistant) | NCT02098343, NCT03268382 (biomarker ID) |
Kevetrin | p53 | Phase II | Ovarian cancers | NCT03042702 |
DPX-Survivac | Survivin peptide attached to an adjuvant | Phase II | Ovarian cancers | NCT03836352, NCT03029403 |
OTX008 | Galectin-1 | Phase I | Solid tumors | NCT01724320 |
CPI-613 | Alternative metabolic pathways | Phase III | Solid tumors | NCT03504423 (pancreatic) |
CPI-613 | Alternative metabolic pathways | Phase II | Lymphoma/Leukemia | NCT03793140 |
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Al-Alem, L.F.; Baker, A.T.; Pandya, U.M.; Eisenhauer, E.L.; Rueda, B.R. Understanding and Targeting Apoptotic Pathways in Ovarian Cancer. Cancers 2019, 11, 1631. https://doi.org/10.3390/cancers11111631
Al-Alem LF, Baker AT, Pandya UM, Eisenhauer EL, Rueda BR. Understanding and Targeting Apoptotic Pathways in Ovarian Cancer. Cancers. 2019; 11(11):1631. https://doi.org/10.3390/cancers11111631
Chicago/Turabian StyleAl-Alem, Linah F., Andrew T. Baker, Unnati M. Pandya, Eric L. Eisenhauer, and Bo R. Rueda. 2019. "Understanding and Targeting Apoptotic Pathways in Ovarian Cancer" Cancers 11, no. 11: 1631. https://doi.org/10.3390/cancers11111631