Rho GTPases in Gynecologic Cancers: In-Depth Analysis toward the Paradigm Change from Reactive to Predictive, Preventive, and Personalized Medical Approach Benefiting the Patient and Healthcare
Abstract
1. Introduction
1.1. Rho GTPase Characteristics and Classification
1.2. Rho GTPases Structure
1.3. Rho GTPases Function
1.4. Rho GTPases Regulation
1.5. The Role of GTPases in Tumorigenesis
2. Rho GTPases in Gynecological Cancer
2.1. Ovarian Cancer
2.2. Endometrial Cancer
2.3. Cervical Cancer
2.4. Breast Cancer
3. A Role of Rho GTPases in Cancer Therapy
3.1. ROCK Inhibitors
3.1.1. Y-27632
3.1.2. Fasudil
3.1.3. Phytochemicals
3.2. RhoA, Rac1, and Cdc42 Inhibitors
3.2.1. Ketorolac
3.2.2. NSC23766
3.2.3. Berberine
3.3. Farnesyltransferase Inhibitors and Geranylgeranyltransferase Inhibitor
3.4. Rho Regulators Inhibitors
4. Prognostic Value of Rho GTPases: Spectacular Biomarkers or “Blind Alley” of Personalized Medicine
5. Towards Predictive, Preventive, and Personalized Medical (PPPM/3PM) Approaches in Gynecological Oncology: Prominent Examples Involving Rho GTPases as a Target
5.1. Rho GTPases in Prediction of Aggressive Gynecologic Cancers and Metastatic Disease: Prominent Examples
5.1.1. Rho GTPases as a Target for Early Detection of Pre/Cancerous Lesions in High Mammographic Density Breast
5.1.2. Predictive Diagnosis of Breast Cancer Based on RhoA Patterns: Multiomics Approach
5.2. Targeted Prevention
5.2.1. Inflammation
5.2.2. Chronic Wounds and Impaired Healing
5.2.3. Rho GTPases-Based Prevention of Endometrial Carcinoma in Obese Phenotype
5.2.4. Small GTPases are Regulated by Nutrients—An Approach for Dietary Cancer Prevention
5.2.5. Targeted Chemoprevention
5.3. Personalized Treatment Algorithms
- -
- Personalized preventive measures applied to suboptimal health;
- -
- Personalized primary cancer prevention and treatments at the level of pre-cancerous lesions;
- -
- Personalized treatment of cancer;
- -
- Personalized secondary prevention (e.g., prevention of cancer in obese and diabetic patients);
- -
6. Conclusions
Funding
Conflicts of Interest
References
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Therapeutics | Cancer Types | Target | Reference |
---|---|---|---|
Y-27632 | Cervical CaSki cells | ↓ ROCK-1, ↑ RhoC | [170] |
Cervical SiHa cells | ↓ ROCK-2 | [171] | |
Ovarian CAOV-3, PA-1 cells | ↓ LPA | [173] | |
Endometrial HEC-1A cells | Reversed effect on LPA and calpeptin-induced cell proliferation | [174] | |
C3 + Y-27632 | Ovarian OVCAR3, SKOV-3, CAOV-3 cells | ↓ leptin-induced uPA | [172] |
Fasudil | Ovarian SKOV-3ip1 cells and xenografts | ↓ intracellular cytoskeletal rearrangement, ↓ tyrosine phosphorylation of paxillin, ↓ serine phosphorylation of myosin light chain | [176] |
Ovarian A2780 cells | Modulation of HIF-1α | [166] | |
NSC23766 | Cervical C33A, SiHa cells | ↓ Rac1 | [133] |
Rhein | Ovarian SKOV-3-PM4 | Modulation of MMPs and Rac1/ROS/MAPK/AP-1 | [183] |
R-ketorolac | Ovarian SKOV-3ip and primary patients derived ovarian cancer cells | Similar effect as NSC23766 and CID2950007/ML141 | [71] |
Racemic ketorolac | Ovarian cancer patients | ↓ Rac1, ↓ Cdc42 | [70] |
R-naproxen | Ovarian OvCa429, OvCa433, cervical HeLa T4 + cells | ↓ Rac1, ↓ Cdc42 | [180] |
ML-141 | Ovarian A2780 cells | ↓ Cdc42 | [182] |
Curcumin | Ovarian SKOV-3 cells | Activation of RhoA/Rho-kinase signaling | [177] |
Resveratrol | Ovarian OVCAR-3 cells | ↓ ARH-I, ↓ LC3-positive autophagic vacuoles formation | [178] |
Type of Cancer | Type of Study | Prognostic Markers | Effect | References |
---|---|---|---|---|
clinical trial (n = 42) | ↑ RhoA, RhoC | higher tumor stages, metastasis spreading | [201] | |
clinical trial (n = 117) | ↓ RacGAP1 | lower risk of recurrence, better overall survival | [203] | |
clinical trial (n = 85) | ↓ ARHGAP26 | lower overall survival, poor prognosis | [204] | |
clinical trial (n = 75) | ↓ ARHGAP10 | lower overall survival | [205] | |
clinical trial (n = 150) | ↑ Rac1 | poor prognosis, risk of recurrence | [206] | |
clinical trial (n = 330) | ↑ Tiam1 | association with clinical stage, histological grade, lower overall survival | [207] | |
in vitro (OVCAR3) clinical study (n = 80) | ↑ SMURF1 | lower overall survival | [208] | |
in vivo (BALB/C nude mice) | ↑ miR-106b | suppression of tumor development and progression | [213] | |
OC | in vitro (OVCAR3, SKOV3/DDP, HO8910-PM) in vivo (BALB/C nude mice) | ↑ miR-93-5p | suppression of tumorigenesis and cancer progression | [214] |
in vitro (JHOC-5, JHOC-7, JHOC8, JHOS-2, JHOS-3, JHOS-4, JHOM-1, OVCAR3) | ↑ miR-10b | acquisition of metastatic phenotypes | [215] | |
clinical trial (n = 74) | ↓ miR-145 | poor prognosis | [216] | |
in vitro (SKOV3, HO8910, ES-2, CAOVR3, OVCAR3, A2780 and A2780PTX) | ↑ miR-519d | reversion of oncogenic effect of E2F1 | [217] | |
in vitro (OVCAR3) | ↑ miR-208a-5p | suppression of cell migration and invasion | [219] | |
clinical trial (n = 46) | ↓ miR-139-5p | correlation with FIGO stage, lymph node metastasis, poor overall survival | [218] | |
CC | clinical trial (n = 195) | ↑ Cdc42 | association with clinical stage of tumors | [134] |
clinical trial (n = 49) | ↑ RhoA | prediction of distant metastasis after chemotherapy | [209] | |
clinical trial (n = 80) | ↑ RhoA | vascular invasion and metastasis | [132] | |
clinical trial (n = 298) | ↑ Tiam1 | advanced clinical stage, metastasis spreading, HPV infection, poor overall survival | [210] | |
in vitro (SiHa, HeLa) | ↑ miR-217 | reduction colony formation, invasion, increased apoptosis | [223] | |
in vitro (HeLa) | ↑ miR-200b | inhibition of EMT | [222] | |
in vitro (C33) | ↑ miR-143-3p | positive regulation of cancer progression | ||
EC | clinical trial (n = 364) | ↑ MIIP | advanced clinical stage, lymph node metastasis | [94] |
clinical trial (n = 265) | ↑ Vav3 | no significant with clinic pathological features and prognostic outcomes for patients | [212] | |
in vitro (HEC-1B) in vivo (BALB/C nude mice) | ↑ miR-372 | suppression of tumorigenesis | [220] | |
in vitro (HEC50, AN3CA) | ↑ miR-200c | inhibition of cell motility and anoikis resistance | [221] |
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Zubor, P.; Dankova, Z.; Kolkova, Z.; Holubekova, V.; Brany, D.; Mersakova, S.; Samec, M.; Liskova, A.; Koklesova, L.; Kubatka, P.; et al. Rho GTPases in Gynecologic Cancers: In-Depth Analysis toward the Paradigm Change from Reactive to Predictive, Preventive, and Personalized Medical Approach Benefiting the Patient and Healthcare. Cancers 2020, 12, 1292. https://doi.org/10.3390/cancers12051292
Zubor P, Dankova Z, Kolkova Z, Holubekova V, Brany D, Mersakova S, Samec M, Liskova A, Koklesova L, Kubatka P, et al. Rho GTPases in Gynecologic Cancers: In-Depth Analysis toward the Paradigm Change from Reactive to Predictive, Preventive, and Personalized Medical Approach Benefiting the Patient and Healthcare. Cancers. 2020; 12(5):1292. https://doi.org/10.3390/cancers12051292
Chicago/Turabian StyleZubor, Pavol, Zuzana Dankova, Zuzana Kolkova, Veronika Holubekova, Dusan Brany, Sandra Mersakova, Marek Samec, Alena Liskova, Lenka Koklesova, Peter Kubatka, and et al. 2020. "Rho GTPases in Gynecologic Cancers: In-Depth Analysis toward the Paradigm Change from Reactive to Predictive, Preventive, and Personalized Medical Approach Benefiting the Patient and Healthcare" Cancers 12, no. 5: 1292. https://doi.org/10.3390/cancers12051292
APA StyleZubor, P., Dankova, Z., Kolkova, Z., Holubekova, V., Brany, D., Mersakova, S., Samec, M., Liskova, A., Koklesova, L., Kubatka, P., Bujnak, J., Kajo, K., Mlyncek, M., Giordano, F. A., & Golubnitschaja, O. (2020). Rho GTPases in Gynecologic Cancers: In-Depth Analysis toward the Paradigm Change from Reactive to Predictive, Preventive, and Personalized Medical Approach Benefiting the Patient and Healthcare. Cancers, 12(5), 1292. https://doi.org/10.3390/cancers12051292