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Melanoma Stem Cell Maintenance And Chemo-resistance Are Mediated By CD133 Signal To PI3K-dependent Pathways
Siraj M. El Jamal, Abdulhadi A. Alamodi, Renate U. Wahl, Z. Grada, M. Shareef, Sofie-Yasmin Hassan, Fadi Murad, Sarah-Lilly Hassan, S. Santourlidis, C. R. Gomez, Y. Haîkel, M. Megahed, M. Hassan
Published 2020 · Biology, Medicine
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Melanoma stem cells (MSCs) are characterized by their unique cell surface proteins and aberrant signaling pathways. These stemness properties are either in a causal or consequential relationship to melanoma progression, treatment resistance and recurrence. The functional analysis of CD133 + and CD133 − cells in vitro and in vivo revealed that melanoma progression and treatment resistance are the consequences of CD133 signal to PI3K pathway. CD133 signal to PI3K pathway drives two downstream pathways, the PI3K/Akt/MDM2 and the PI3K/Akt/MKP-1 pathways. Activation of PI3K/Akt/MDM2 pathway results in the destabilization of p53 protein, while the activation of PI3K/Akt/MKP-1 pathway results in the inhibition of mitogen-activated protein kinases (MAPKs) JNK and p38. Activation of both pathways leads to the inhibition of fotemustine-induced apoptosis. Thus, the disruption of CD133 signal to PI3K pathway is essential to overcome Melanoma resistance to fotemustine. The pre-clinical verification of in vitro data using xenograft mouse model of MSCs confirmed the clinical relevance of CD133 signal as a therapeutic target for melanoma treatment. In conclusion, our study provides an insight into the mechanisms regulating MSCs growth and chemo-resistance and suggested a clinically relevant approach for melanoma treatment.
This paper references
Regulatory Network of ARF in Cancer Development
A. Ko (2018)
The proteasome: Overview of structure and functions
K. Tanaka (2009)
The oncoprotein HBXIP promotes human breast cancer growth through down-regulating p53 via miR-18b/MDM2 and pAKT/MDM2 pathways
H. Li (2018)
Akt Signaling Leads to Stem Cell Activation and Promotes Tumor Development in Epidermis
C. Segrelles (2014)
Potential mechanisms of CD133 in cancer stem cells
J. Jang (2017)
Crosstalk Between Apoptosis and Autophagy: Molecular Mechanisms and Therapeutic Strategies in Cancer
A. Elkhattouti (2013)
Apoptosis related protein-1 triggers melanoma cell death via interaction with the juxtamembrane region of p75 neurotrophin receptor
D. Selimović (2012)
Pokemon enhances proliferation, cell cycle progression and anti-apoptosis activity of colorectal cancer independently of p14ARF–MDM2–p53 pathway
Yi Zhao (2014)
Resistance to receptor tyrosine kinase inhibitors in solid tumors: can we improve the cancer fighting strategy by blocking autophagy?
S. Aveic (2016)
Readministration of Nivolumab after Persistent Immune-related Colitis in a Patient with Recurrent Melanoma
Y. Fujii (2018)
Antitumor activity of curcumin by modulation of apoptosis and autophagy in human lung cancer A549 cells through inhibiting PI3K/Akt/mTOR pathway.
F. Liu (2018)
Resistant mechanisms to BRAF inhibitors in melanoma.
J. Manzano (2016)
CSE1L Links cAMP/PKA and Ras/ERK pathways and regulates the expressions and phosphorylations of ERK1/2, CREB, and MITF in melanoma cells
Woan-Ruoh Lee (2016)
Phenotypic tumour cell plasticity as a resistance mechanism and therapeutic target in melanoma.
A. Rösch (2016)
Elevated Expression of Hepatoma Up‐Regulated Protein Inhibits γ‐Irradiation‐Induced Apoptosis of Prostate Cancer Cells
M. Hassan (2016)
Acquired resistance to BRAF inhibition can confer cross-resistance to combined BRAF/MEK inhibition.
K. Gowrishankar (2012)
Extracellular assembly and activation principles of oncogenic class III receptor tyrosine kinases
K. Verstraete (2012)
Mechanisms of intrinsic and acquired resistance to kinase‐targeted therapies
Shubha Bagrodia (2012)
SOX2 promotes tumor growth of esophageal squamous cell carcinoma through the AKT/mammalian target of rapamycin complex 1 signaling pathway
Y. Gen (2013)
Recombinant methioninase (rMETase) is an effective therapeutic for BRAF-V600E-negative as well as -positive melanoma in patient-derived orthotopic xenograft (PDOX) mouse models
Kei Kawaguchi (2018)
Different expression pattern and significance of p14ARF-Mdm2-p53 pathway and Bmi-1 exist between gastric cardia and distal gastric adenocarcinoma.
Dongying Yao (2013)
SPARC functions as an anti-stress factor by inactivating p53 through Akt-mediated MDM2 phosphorylation to promote melanoma cell survival
N. Fenouille (2011)
β-Catenin mRNA Silencing and MEK Inhibition Display Synergistic Efficacy in Preclinical Tumor Models
S. Ganesh (2017)
The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England
Y. Meng (2018)
Elevated expression of protein tyrosine kinase c-Yes, but not c-Src, in human malignant melanoma.
F. Loganzo (1993)
Divorcing ARF and p53: an unsettled case
C. Sherr (2006)
Imiquimod‐induced apoptosis of melanoma cells is mediated by ER stress‐dependent Noxa induction and enhanced by NF‐κB inhibition
A. Elkhattouti (2016)
Adjuvant vemurafenib in resected, BRAF
M Maio (2018)
Cyclin-dependent kinase 1-mediated phosphorylation of YES links mitotic arrest and apoptosis during antitubulin chemotherapy.
Z. Wang (2018)
Oligomerization-induced Modulation of TPR-MET Tyrosine Kinase Activity*
John L. Hays (2003)
Deregulation of the p14ARF/MDM2/p53 pathway is a prerequisite for human astrocytic gliomas with G1-S transition control gene abnormalities.
K. Ichimura (2000)
Interferon gamma-induced apoptosis of head and neck squamous cell carcinoma is connected to indoleamine-2,3-dioxygenase via mitochondrial and ER stress-associated pathways
S. E. El Jamal (2016)
High-Throughput Analysis of Mammalian Receptor Tyrosine Kinase Activation in Yeast Cells.
Nobuo Yoshimoto (2017)
Ectopic overexpression of CD133 in HNSCC makes it resistant to commonly used chemotherapeutics
Junyoung Lee (2017)
AXL receptor signalling suppresses p53 in melanoma through stabilization of the MDMX–MDM2 complex
A. De Polo (2017)
Stimulation of the protein tyrosine kinase c-Yes but not c-Src by neurotrophins in human brain-metastatic melanoma cells
D. Marchetti (1998)
Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms.
D. Johnson (2015)
Contact by melanoma cells causes malignant transformation of human epithelial-like stem cells via alpha V integrin activation of transforming growth factor β1 signaling
Hongyu Sun (2011)
HMGA2 promotes intestinal tumorigenesis by facilitating MDM2‐mediated ubiquitination and degradation of p53
Y. Wang (2018)
Recent advances in genitourinary tumors: A review focused on biology and systemic treatment.
A. González del Alba (2017)
Effects of Four Chemotherapeutic Agents, Bleomycin, Etoposide, Cisplatin, and Cyclophosphamide, on DNA Damage and Telomeres in a Mouse Spermatogonial Cell Line1
M. Liu (2014)
Tyrosine kinase Fyn regulates iNOS expression in LPS-stimulated astrocytes via modulation of ERK phosphorylation.
H. Ko (2018)
MDM4 is a key therapeutic target in cutaneous melanoma
A. Gembarska (2012)
Signaling through scaffold, anchoring, and adaptor proteins.
T. Pawson (1997)
Health-related quality of life impact in a randomised phase III study of the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma.
D. Schadendorf (2015)
Tumor microenvironment changes leading to resistance of immune checkpoint inhibitors in metastatic melanoma and strategies to overcome resistance
Bhargavi Pulluri (2017)
Up-Regulation of PI 3-Kinases and the Activation of PI3K-Akt Signaling Pathway in Cancer Stem-Like Cells Through DNA Hypomethylation Mediated by the Cancer Microenvironment
Aung Ko Ko Oo (2018)
Adjuvant vemurafenib in resected
M Maio (2018)
Registered Report: COT drives resistance to RAF inhibition through MAP kinase pathway reactivation
Vidhu Sharma (2016)
Reactivation of Mitogen-activated Protein Kinase (MAPK) Pathway by FGF Receptor 3 (FGFR3)/Ras Mediates Resistance to Vemurafenib in Human B-RAF V600E Mutant Melanoma*
Vipin Yadav (2012)
Receptor tyrosine kinases and their activation in melanoma
D. Easty (2011)
BRAF inhibitor discontinuation and rechallenge in advanced melanoma patients with a complete initial treatment response
C. Desvignes (2017)
LRP6 targeting suppresses gastric tumorigenesis via P14ARF–Mdm2–P53-dependent cellular senescence
H. Wang (2017)
Gq-Induced Apoptosis is Mediated by AKT Inhibition That Leads to PKC-Induced JNK Activation
Guy Nadel (2018)
Temozolomide in combination with interferon-alfa versus temozolomide alone in patients with advanced metastatic melanoma: a randomized, phase III, multicenter study from the Dermatologic Cooperative Oncology Group.
R. Kaufmann (2005)
Nogo-B receptor promotes the chemoresistance of human hepatocellular carcinoma via the ubiquitination of p53 protein
Chengyong Dong (2016)
Notch1-MAPK Signaling Axis Regulates CD133+ Cancer Stem Cell-Mediated Melanoma Growth and Angiogenesis.
D. Kumar (2016)
PTPN11 Is a Central Node in Intrinsic and Acquired Resistance to Targeted Cancer Drugs.
A. Prahallad (2015)
Negative immune checkpoint regulation by VISTA: a mechanism of acquired resistance to anti-PD-1 therapy in metastatic melanoma patients
H. Kakavand (2017)
Genetics and epigenetics of cutaneous malignant melanoma: a concert out of tune.
K. van den Hurk (2012)
ABCG2 is required for self-renewal and chemoresistance of CD133-positive human colorectal cancer cells
L. Ma (2016)
Genetic and pharmacologic evidence implicating the p85 alpha, but not p85 beta, regulatory subunit of PI3K and Rac2 GTPase in regulating oncogenic KIT-induced transformation in acute myeloid leukemia and systemic mastocytosis.
V. Munugalavadla (2007)
Activation of PI3K/Akt pathway by CD133-p85 interaction promotes tumorigenic capacity of glioma stem cells
Y. Wei (2013)
Activated MEK cooperates with Cdkn2a and Pten loss to promote the development and maintenance of melanoma
H. Yang (2017)
Clinical Response Rates From Interleukin-2 Therapy for Metastatic Melanoma Over 30 Years’ Experience: A Meta-Analysis of 3312 Patients
R. Bright (2017)
Identification and analysis of CD133(+) melanoma stem-like cells conferring resistance to taxol: An insight into the mechanisms of their resistance and response.
A. Elkhattouti (2014)
Bortezomib/proteasome inhibitor triggers both apoptosis and autophagy-dependent pathways in melanoma cells.
D. Selimović (2013)
Adaptation of cancer cells from different entities to the MDM2 inhibitor nutlin-3 results in the emergence of p53-mutated multi-drug-resistant cancer cells
M. Michaelis (2011)
CD133⁺ melanoma subpopulation acquired resistance to caffeic acid phenethyl ester-induced apoptosis is attributed to the elevated expression of ABCB5: significance for melanoma treatment.
A. Elkhattouti (2015)
High frequency of p16 and p14 promoter hypermethylation and marked telomere instability in salivary gland tumors.
N. Nikolic (2015)
The cost-effectiveness of nivolumab monotherapy for the Melanoma stem cell maintenance and chemo-resistance are mediated by CD133 signal to PI3K-dependent
Y Meng (2018)
The BH3-only member Noxa causes apoptosis in melanoma cells by multiple pathways
M. Hassan (2008)
The clinical features, treatment, and prognosis of primary mediastinal malignant melanoma
Z. Li (2017)
Correction: NLRP6 targeting suppresses gastric tumorigenesis via P14ARF–Mdm2–P53-dependent cellular senescence
H. Wang (2018)
Adjuvant vemurafenib in resected, BRAFV600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.
M. Maio (2018)
Receptor tyrosine kinases and their activation in melanoma. Pigment
D J Easty (2011)
Phase 1 dose-escalation study of IV ixazomib, an investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma
S. Assouline (2014)
Aberrant apoptotic machinery confers melanoma dual resistance to BRAF(V600E) inhibitor and immune effector cells: immunosensitization by a histone deacetylase inhibitor.
A. Jazirehi (2014)
A Multicenter Phase I Dose Escalation Trial to Evaluate Safety and Tolerability of Intra-arterial Temozolomide for Patients with Advanced Extremity Melanoma Using Normothermic Isolated Limb Infusion
G. Beasley (2014)
Corrigendum to "Bortezomib/proteasome inhibitor triggers both apoptosis and autophagy-dependent pathways in melanoma cells". [Cell Signal. 25(1)Jan 2013 308-18].
D. Selimović (2015)
This paper is referenced by
CD133 Antigen as a Potential Marker of Melanoma Stem Cells: In Vitro and In Vivo Studies
T. Kloskowski (2020)