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.
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Roesch A, Paschen A, Landsberg J, Helfrich I, Becker JC, Schadendorf D. Phenotypic tumour cell plasticity as a resistance mechanism and therapeutic target in melanoma. Eur J Cancer. 2016;59:109–12.
Li Z, Jia H, Zhang B, Zhang Y, Li H, Song P. The clinical features, treatment, and prognosis of primary mediastinal malignant melanoma: a case report. Med (Baltim). 2017;96:e6436.
El-Khattouti A, Sheehan NT, Monico J, Drummond HA, Haikel Y, Brodell RT, et al. CD133+ melanoma subpopulation acquired resistance to caffeic acid phenethyl ester-induced apoptosis is attributed to the elevated expression of ABCB5: significance for melanoma treatment. Cancer Lett. 2015;357:83–104.
Kumar D, Kumar S, Gorain M, Tomar D, Patil HS, Radharani NNV, et al. Notch1-MAPK signaling axis regulates CD133(+) cancer stem cell-mediated melanoma growth and angiogenesis. J Invest Dermatol. 2016;136:2462–74.
Sun H, Hu K, Wu M, Xiong J, Yuan L, Tang Y, et al. Contact by melanoma cells causes malignant transformation of human epithelial-like stem cells via alpha V integrin activation of transforming growth factor β1 signaling. Exp Biol Med (Maywood). 2011;236:352–65.
Beasley GM, Speicher P, Augustine CK, Dolber PC, Peterson BL, Sharma K, et al. 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. Ann Surg Oncol. 2015;22:287–94.
Yang H, Kircher DA, Kim KH, Grossmann AH, VanBrocklin MW, Holmen SL, et al. Activated MEK cooperates with Cdkn2a and Pten loss to promote the development and maintenance of melanoma. Oncogene. 2017;36:3842–51.
Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA, et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010;468:968–72.
Kakavand H, Jackett LA, Menzies AM, Gide TN, Carlino MS, Saw RPM, et al. Negative immune checkpoint regulation by VISTA: a mechanism of acquired resistance to anti-PD-1 therapy in metastatic melanoma patients. Mod Pathol. 2017;30:1666–76.
van den Hurk K, Niessen HE, Veeck J, van den Oord JJ, van Steensel MA, Zur Hausen A, et al. Genetics and epigenetics of cutaneous malignant melanoma: a concert out of tune. Biochim Biophys Acta. 2012;1826:89–102.
Pulluri B, Kumar A, Shaheen M, Jeter J, Sundararajan S. Tumor microenvironment changes leading to resistance of immune checkpoint inhibitors in metastatic melanoma and strategies to overcome resistance. Pharm Res. 2017;123:95–102.
Yadav V, Zhang X, Liu J, Estrem S, Li S, Gong XQ, et al. 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. J Biol Chem. 2012;287:28087–98.
Gowrishankar K, Snoyman S, Pupo GM, Becker TM, Kefford RF, Rizos H. Acquired resistance to BRAF inhibition can confer cross-resistance to combined BRAF/MEK inhibition. J Invest Dermatol. 2012;132:1850–9.
Johnson DB, Menzies AM, Zimmer L, Eroglu Z, Ye F, Zhao S, et al. Acquired BRAF inhibitor resistance: a multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms. Eur J Cancer. 2015;51:2792–9.
Easty DJ, Gray SG, O’Byrne KJ, O’Donnell D, Bennett DC. Receptor tyrosine kinases and their activation in melanoma. Pigment Cell Melanoma Res. 2011;24:446–61.
Marchetti D, Parikh N, Sudol M, Gallick GE. Stimulation of the protein tyrosine kinase c-Yes but not c-Src by neurotrophins in human brain-metastatic melanoma cells. Oncogene. 1998;16:3253–60.
Loganzo F, Dosik JS, Zhao Y, Vidal MJ, Nanus DM, Sudol M, et al. Elevated expression of protein tyrosine kinase c-Yes, but not c-Src, in human malignant melanoma. Oncogene. 1993;8:2637–44.
Pawson T, Scott JD. Signaling through scaffold, anchoring, and adaptor proteins. Science. 1997;278:2075–80.
Wang Z, Chen X, Zhong MZ, Yang S, Zhou J, Klinkebiel DL, et al. Cyclin-dependent kinase 1-mediated phosphorylation of YES links mitotic arrest and apoptosis during antitubulin chemotherapy. Cell Signal. 2018;52:137–46.
Verstraete K, Savvides SN. Extracellular assembly and activation principles of oncogenic class III receptor tyrosine kinases. Nat Rev Cancer. 2012;12:753–66.
González Del Alba A, Arranz JÁ, Puente J, Méndez-Vidal MJ, Gallardo E, et al. Recent advances in genitourinary tumors: a review focused on biology and systemic treatment. Crit Rev Oncol Hematol. 2017;113:171–90.
Aveic S, Tonini GP. Resistance to receptor tyrosine kinase inhibitors in solid tumors: can we improve the cancer fighting strategy by blocking autophagy? Cancer Cell Int. 2016;16:62.
Ko HM, Lee SH, Bang M, Kim KC, Jeon SJ, Park YM, et al. Tyrosine kinase Fyn regulates iNOS expression in LPS-stimulated astrocytes via modulation of ERK phosphorylation. Biochem Biophys Res Commun. 2018;495:1214–20.
Yoshimoto N, Kuroda S. High-throughput analysis of mammalian receptor tyrosine kinase activation in yeast cells. Methods Mol Biol. 2017;1487:35–52.
Hays JL, Watowich SJ. Oligomerization-induced modulation of TPR-MET tyrosine kinase activity. J Biol Chem. 2003;278:27456–63.
Wei Y, Jiang Y, Zou F, Liu Y, Wang S, Xu N, et al. Activation of PI3K/Akt pathway by CD133-p85 interaction promotes tumorigenic capacity of glioma stem cells. Proc Natl Acad Sci USA. 2013;110:6829–34.
Munugalavadla V, Sims EC, Borneo J, Chan RJ, Kapur R. 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. Blood. 2007;110:1612–20.
Lee J, Park M, Ko Y, Kim B, Kim O, Hyun H, et al. Ectopic overexpression of CD133 in HNSCC makes it resistant to commonly used chemotherapeutics. Tumour Biol. 2017;39:1010428317695534.
Ma L, Liu T, Jin Y, Wei J, Yang Y, Zhang H. ABCG2 is required for self-renewal and chemoresistance of CD133-positive human colorectal cancer cells. Tumour Biol. 2016;37:12889–96.
Jang JW, Song Y, Kim SH, Kim J, Seo HR. Potential mechanisms of CD133 in cancer stem cells. Life Sci. 2017;184:25–29.
Manzano JL, Bugés C, de Los Llanos Gil M, Vila L, Martínez-Balibrea E, Martínez-Cardús A. Resistant mechanisms to BRAF inhibitors in melanoma. Ann Transl Med. 2016;4:237.
Prahallad A, Heynen GJ, Germano G, Willems SM, Evers B, Vecchione L, et al. PTPN11 is a central node in intrinsic and acquired resistance to targeted cancer drugs. Cell Rep. 2015;12:1978–85.
Bagrodia S, Smeal T, Abraham RT. Mechanisms of intrinsic and acquired resistance to kinase-targeted therapies. Pigment Cell Melanoma Res. 2012;25:819–31.
Jazirehi AR, Nazarian R, Torres-Collado AX, Economou JS. Aberrant apoptotic machinery confers melanoma dual resistance to BRAF(V600E) inhibitor and immune effector cells: immunosensitization by a histone deacetylase inhibitor. Am J Clin Exp Immunol. 2014;3:43–56.
Meng Y, Hertel N, Ellis J, Morais E, Johnson H, Philips Z, et al. The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England. Eur J Health Econ. 2018;19:1163–72.
Schadendorf D, Amonkar MM, Stroyakovskiy D, Levchenko E, Gogas H, de Braud F, et al. 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. Eur J Cancer. 2015;51:833–40.
Fujii Y, Nishikawa Y, Nomura M, Miyamoto S, Uneno Y, Horimatsu T, et al. Readministration of Nivolumab after persistent immune-related colitis in a patient with recurrent melanoma. Intern Med. 2018;57:1173–6.
Maio M, Lewis K, Demidov L, Mandalà M, Bondarenko I, Ascierto PA, et al. Adjuvant vemurafenib in resected, BRAF. Lancet Oncol. 2018;19:510–20.
Kawaguchi K, Igarashi K, Li S, Han Q, Tan Y, Miyake K, et al. Recombinant methioninase (rMETase) is an effective therapeutic for BRAF-V600E-negative as well as -positive melanoma in patient-derived orthotopic xenograft (PDOX) mouse models. Oncotarget. 2018;9:915–23.
Ganesh S, Shui X, Craig KP, Koser ML, Chopda GR, Cyr WA, et al. β-Catenin mRNA silencing and MEK inhibition display synergistic efficacy in preclinical tumor models. Mol Cancer Ther. 2018;17:544–53.
Desvignes C, Abi Rached H, Templier C, Drumez E, Lepesant P, Desmedt E, et al. BRAF inhibitor discontinuation and rechallenge in advanced melanoma patients with a complete initial treatment response. Melanoma Res. 2017;27:281–7.
Bright R, Coventry BJ, Eardley-Harris N, Briggs N. Clinical response rates from Interleukin-2 therapy for metastatic melanoma over 30 years’ experience: a meta-analysis of 3312 patients. J Immunother. 2017;40:21–30.
Kaufmann R, Spieth K, Leiter U, Mauch C, von den Driesch P, Vogt T, et al. 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. J Clin Oncol. 2005;23:9001–7.
El-Khattouti A, Selimovic D, Haïkel Y, Megahed M, Gomez CR, Hassan M. Identification and analysis of CD133(+) melanoma stem-like cells conferring resistance to taxol: an insight into the mechanisms of their resistance and response. Cancer Lett. 2014;343:123–33.
Hassan M, El Khattouti A, Ejaeidi A, Ma T, Day WA, Espinoza I, et al. Elevated expression of hepatoma up-regulated protein inhibits γ-irradiation-induced apoptosis of prostate cancer cells. J Cell Biochem. 2016;117:1308–18.
Liu M, Hales BF, Robaire B. Effects of four chemotherapeutic agents, bleomycin, etoposide, cisplatin, and cyclophosphamide, on DNA damage and telomeres in a mouse spermatogonial cell line. Biol Reprod. 2014;90:72.
El-Khattouti A, Selimovic D, Hannig M, Taylor EB, Abd Elmageed ZY, Hassan SY, et al. Imiquimod-induced apoptosis of melanoma cells is mediated by ER stress-dependent Noxa induction and enhanced by NF-κB inhibition. J Cell Mol Med. 2016;20:266–86.
El-Khattouti A, Selimovic D, Haikel Y, Hassan M. Crosstalk between apoptosis and autophagy: molecular mechanisms and therapeutic strategies in cancer. J Cell Death. 2013;6:37–55.
Ko A, Han SY, Song J. Regulatory Network of ARF in Cancer Development. Mol Cells. 2018;41:381–9.
Nikolic N, Anicic B, Carkic J, Simonovic J, Toljic B, Tanic N, et al. High frequency of p16 and p14 promoter hypermethylation and marked telomere instability in salivary gland tumors. Arch Oral Biol. 2015;60:1662–6.
Sherr CJ. Divorcing ARF and p53: an unsettled case. Nat Rev Cancer. 2006;6:663–73.
Ichimura K, Bolin MB, Goike HM, Schmidt EE, Moshref A, Collins VP. Deregulation of the p14ARF/MDM2/p53 pathway is a prerequisite for human astrocytic gliomas with G1-S transition control gene abnormalities. Cancer Res. 2000;60:417–24.
Zhao Y, Yao YH, Li L, An WF, Chen HZ, Sun LP, et al. Pokemon enhances proliferation, cell cycle progression and anti-apoptosis activity of colorectal cancer independently of p14ARF-MDM2-p53 pathway. Med Oncol. 2014;31:288.
Yao D, Wang Y, Xue L, Wang H, Zhang J, Zhang X. Different expression pattern and significance of p14ARF-Mdm2-p53 pathway and Bmi-1 exist between gastric cardia and distal gastric adenocarcinoma. Hum Pathol. 2013;44:844–51.
Wang H, Xu G, Huang Z, Li W, Cai H, Zhang Y, et al. Correction: NLRP6 targeting suppresses gastric tumorigenesis via P14. Oncotarget. 2018;9:35512.
Gembarska A, Luciani F, Fedele C, Russell EA, Dewaele M, Villar S, et al. MDM4 is a key therapeutic target in cutaneous melanoma. Nat Med. 2012;18:1239–47.
Michaelis M, Rothweiler F, Barth S, Cinatl J, van Rikxoort M, Löschmann N, et al. 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. Cell Death Dis. 2011;2:e243.
de Polo A, Luo Z, Gerarduzzi C, Chen X, Little JB, Yuan ZM. AXL receptor signalling suppresses p53 in melanoma through stabilization of the MDMX-MDM2 complex. J Mol Cell Biol. 2017;9:154–65.
Tanaka K. The proteasome: overview of structure and functions. Proc Jpn Acad Ser B Phys Biol Sci. 2009;85:12–36.
Assouline SE, Chang J, Cheson BD, Rifkin R, Hamburg S, Reyes R, et al. Phase 1 dose-escalation study of IV ixazomib, an investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma. Blood Cancer J. 2014;4:e251.
El Jamal SM, Taylor EB, Abd Elmageed ZY, Alamodi AA, Selimovic D, Alkhateeb A, et al. 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. Cell Div. 2016;11:11.
Selimovic D, Porzig BB, El-Khattouti A, Badura HE, Ahmad M, Ghanjati F, et al. Bortezomib/proteasome inhibitor triggers both apoptosis and autophagy-dependent pathways in melanoma cells. Cell Signal. 2013;25:308–18.
Hassan M, Alaoui A, Feyen O, Mirmohammadsadegh A, Essmann F, Tannapfel A, et al. The BH3-only member Noxa causes apoptosis in melanoma cells by multiple pathways. Oncogene. 2008;27:4557–68.
Lee WR, Shen SC, Wu PR, Chou CL, Shih YH, Yeh CM, et al. CSE1L Links cAMP/PKA and Ras/ERK pathways and regulates the expressions and phosphorylations of ERK1/2, CREB, and MITF in melanoma cells. Mol Carcinog. 2016;55:1542–52.
Oo AKK, Calle AS, Nair N, Mahmud H, Vaidyanath A, Yamauchi J, et al. 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. Transl Oncol. 2018;11:653–63.
Gen Y, Yasui K, Nishikawa T, Yoshikawa T. SOX2 promotes tumor growth of esophageal squamous cell carcinoma through the AKT/mammalian target of rapamycin complex 1 signaling pathway. Cancer Sci. 2013;104:810–6.
Segrelles C, García-Escudero R, Garín MI, Aranda JF, Hernández P, Ariza JM, et al. Akt signaling leads to stem cell activation and promotes tumor development in epidermis. Stem Cells. 2014;32:1917–28.
Nadel G, Yao Z, Ben-Ami I, Naor Z, Seger R. Gq-induced apoptosis is mediated by AKT inhibition that leads to PKC-induced JNK activation. Cell Physiol Biochem. 2018;50:121–35.
Liu F, Gao S, Yang Y, Zhao X, Fan Y, Ma W, et al. Antitumor activity of curcumin by modulation of apoptosis and autophagy in human lung cancer A549 cells through inhibiting PI3K/Akt/mTOR pathway. Oncol Rep. 2018;39:1523–31.
Fenouille N, Puissant A, Tichet M, Zimniak G, Abbe P, Mallavialle A, et al. SPARC functions as an anti-stress factor by inactivating p53 through Akt-mediated MDM2 phosphorylation to promote melanoma cell survival. Oncogene. 2011;30:4887–900.
Dong C, Zhao B, Long F, Liu Y, Liu Z, Li S, et al. Nogo-B receptor promotes the chemoresistance of human hepatocellular carcinoma via the ubiquitination of p53 protein. Oncotarget. 2016;7:8850–65.
Li H, Wang Z, Jiang M, Fang RP, Shi H, Shen Y, et al. The oncoprotein HBXIP promotes human breast cancer growth through down-regulating p53 via miR-18b/MDM2 and pAKT/MDM2 pathways. Acta Pharm Sin. 2018;39:1787–96.
Wang Y, Hu L, Wang J, Li X, Sahengbieke S, Wu J, et al. HMGA2 promotes intestinal tumorigenesis by facilitating MDM2-mediated ubiquitination and degradation of p53. J Pathol. 2018;246:508–18.
Selimovic D, Sprenger A, Hannig M, Haïkel Y, Hassan M. Apoptosis related protein-1 triggers melanoma cell death via interaction with the juxtamembrane region of p75 neurotrophin receptor. J Cell Mol Med. 2012;16:349–61.
This work was supported by grants from German Research Foundation (HA 5081/3-1), from L’ Alsace contre le cancer, France, German cancer research foundation (10-2202-Ha 1) to MH.
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Jamal, S.M.E., Alamodi, A., Wahl, R.U. et al. Melanoma stem cell maintenance and chemo-resistance are mediated by CD133 signal to PI3K-dependent pathways. Oncogene 39, 5468–5478 (2020). https://doi.org/10.1038/s41388-020-1373-6