YAP activation in melanoma contributes to anoikis resistance and metastasis

2020 ◽  
pp. 153537022097710
Author(s):  
Bei Zhao ◽  
Jun Xie ◽  
Xiyuan Zhou ◽  
Lixia Zhang ◽  
Xiankui Cheng ◽  
...  
Keyword(s):  
Hippo Pathway ◽  
Metastatic Potential ◽  
Melanoma Cells ◽  
Anoikis Resistance ◽  
Protein Activation ◽  
Protein Inhibition ◽  
Cell Invasiveness ◽  
Protein Transcription ◽  
Dose Dependent ◽  
Resistant Cells

Melanoma is inherently heterogeneous, providing resistance to apoptosis. Anoikis resistance is a hallmark feature of metastatic melanoma to escape apoptosis when cells lose contact with adjacent cells or extracellular matrix. The yes-associated protein transcription co-activator is the effector of Hippo pathway. Herein, we investigated the function of yes-associated protein in anoikis resistance of melanoma cells. When melanoma cells were grown under anchorage-independent condition, anoikis-resistant cells displayed higher levels of yes-associated protein activation than the cells that were attached to the basement membrane, as evidenced by downregulated phosphorylated yes-associated protein at Ser127 and higher expression of downstream genes BCL2 and MCL-1. Yes-associated protein overexpression directly enhanced the anoikis resistance and metastatic potential of melanoma cells. Conversely, yes-associated protein inhibitor CA3 exhibited Dose-dependent induction of anoikis in resistant melanoma cells and exerted great inhibition on cell migration. Knockdown of yes-associated protein expression by shRNA also rendered melanoma cells susceptible to anoikis and interrupted cell invasiveness. Yes-associated protein inhibition in anoikis-resistant cells also reduced the number of metastatic nodules in the lung sections of SCID mice. Clinically, higher yes-associated protein level in the lung metastasis tissues correlated with higher BCL2 and MCL1 expressions compared with the non-metastasis tissues. Overall, our finding suggests that the aberrant activation of yes-associated protein exerts important role on anoikis resistance and metastatic capability of melanoma cells.

Sequential detection of mRNA for the chemokine IL-8 and macrophages (F4/80) in human melanoma

1995 ◽  
Vol 53 ◽  
pp. 1008-1009
Author(s):  
C.D. Bucana ◽  
R. Sanchez ◽  
R. Singh ◽  
I.J. Fidler
Keyword(s):  
Tumor Cells ◽  
Nude Mice ◽  
Constitutive Expression ◽  
Metastatic Potential ◽  
Melanoma Cells ◽  
Human Melanoma ◽  
Angiogenic Factor ◽  
Infiltrating Cells ◽  
Immunoperoxidase Assay ◽  
Multifunctional Cytokine

The purpose of this study was to demonstrate by ISH the presence of IL-8 mRNA, and by immunohistochemistry (IHC) the presence of the chemokine IL-8 and the distribution of infiltrating macrophages in subcutaneous melanomas in the same tumor. IL-8 is a multifunctional cytokine produced by melanoma cells, activated macrophages and monocytes and it has been shown to be a growth and angiogenic factor for tumor cells. More recently it was shown that constitutive expression of IL-8 correlated directly with metastatic potential of human melanoma cells in nude mice. IL-8 content of a solid tumor as determined by Western blot analysis does not take into account the contribution of macrophages. Previous studies showed that murine tumors contain many infiltrating cells interspersed among tumor cells whereas human tumors growing in nude mice exhibit macrophages at the periphery or between tumor islands. In this study we demonstrate the expression of IL-8 and the distribution of macrophages by immunoperoxidase assay and IL-8 mRNA by ISH.

scholarly journals TRPM2 Oxidation Activates Two Distinct Potassium Channels in Melanoma Cells through Intracellular Calcium Increase

2021 ◽  
Vol 22 (16) ◽  
pp. 8359
Author(s):  
Loretta Ferrera ◽  
Raffaella Barbieri ◽  
Cristiana Picco ◽  
Paolo Zuccolini ◽  
Alessia Remigante ◽  
...  
Keyword(s):  
Intracellular Calcium ◽  
Expression Analysis ◽  
Large Fraction ◽  
Specific Inhibitor ◽  
Metastatic Potential ◽  
Melanoma Cells ◽  
Bk Channels ◽  
Current Increase ◽  
Tumor Microenvironments ◽  
Trpm2 Channel

Tumor microenvironments are often characterized by an increase in oxidative stress levels. We studied the response to oxidative stimulation in human primary (IGR39) or metastatic (IGR37) cell lines obtained from the same patient, performing patch-clamp recordings, intracellular calcium ([Ca2+]i) imaging, and RT-qPCR gene expression analysis. In IGR39 cells, chloramine-T (Chl-T) activated large K+ currents (KROS) that were partially sensitive to tetraethylammonium (TEA). A large fraction of KROS was inhibited by paxilline—a specific inhibitor of large-conductance Ca2+-activated BK channels. The TEA-insensitive component was inhibited by senicapoc—a specific inhibitor of the Ca2+-activated KCa3.1 channel. Both BK and KCa3.1 activation were mediated by an increase in [Ca2+]i induced by Chl-T. Both KROS and [Ca2+]i increase were inhibited by ACA and clotrimazole—two different inhibitors of the calcium-permeable TRPM2 channel. Surprisingly, IGR37 cells did not exhibit current increase upon the application of Chl-T. Expression analysis confirmed that the genes encoding BK, KCa3.1, and TRPM2 are much more expressed in IGR39 than in IGR37. The potassium currents and [Ca2+]i increase observed in response to the oxidizing agent strongly suggest that these three molecular entities play a major role in the progression of melanoma. Pharmacological targeting of either of these ion channels could be a new strategy to reduce the metastatic potential of melanoma cells, and could complement classical radio- or chemotherapeutic treatments.

Effect of Interferon-Gamma on the Expression of HLA-DR by Human Melanoma Cells of Varying Metastatic Potential

1990 ◽  
Vol 3 (3) ◽  
pp. 162-167 ◽  
Author(s):  
MARY J.C. HENDRIX ◽  
ELISABETH A. SEFTOR ◽  
MICHELLE D. ECKES ◽  
ADRIAN L. WINTERS ◽  
STANLEY P.L. LEONG ◽  
...  
Keyword(s):  
Interferon Gamma ◽  
Metastatic Potential ◽  
Melanoma Cells ◽  
Human Melanoma ◽  
Human Melanoma Cells ◽  
Hla Dr

scholarly journals Deregulated FASN Expression in BRAF Inhibitor-Resistant Melanoma Cells Unveils New Targets for Drug Combinations

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2284
Author(s):  
Serena Stamatakos ◽  
Giovanni Luca Beretta ◽  
Elisabetta Vergani ◽  
Matteo Dugo ◽  
Cristina Corno ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Metastatic Melanoma ◽  
Mutant Cell ◽  
Braf Inhibitor ◽  
Cancer Cell Line ◽  
Melanoma Cells ◽  
Melanoma Progression ◽  
Increased Sensitivity ◽  
Resistant Cells

Metabolic changes promoting cell survival are involved in metastatic melanoma progression and in the development of drug resistance. In BRAF-inhibitor resistant melanoma cells, we explored the role of FASN, an enzyme involved in lipogenesis overexpressed in metastatic melanoma. Resistant melanoma cells displaying enhanced migratory and pro-invasive abilities increased sensitivity to the BRAF inhibitor PLX4032 upon the molecular targeting of FASN and upon treatment with the FASN inhibitor orlistat. This behavior was associated with a marked apoptosis and caspase 3/7 activation observed for the drug combination. The expression of FASN was found to be inversely associated with drug resistance in BRAF-mutant cell lines, both in a set of six resistant/sensitive matched lines and in the Cancer Cell Line Encyclopedia. A favorable drug interaction in resistant cells was also observed with U18666 A inhibiting DHCR24, which increased upon FASN targeting. The simultaneous combination of the two inhibitors showed a synergistic interaction with PLX4032 in resistant cells. In conclusion, FASN plays a role in BRAF-mutated melanoma progression, thereby creating novel therapeutic opportunities for the treatment of melanoma.

scholarly journals Inhibition of Mitochondrial Dynamics Preferentially Targets Pancreatic Cancer Cells with Enhanced Tumorigenic and Invasive Potential

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 698
Author(s):  
Sarah Courtois ◽  
Beatriz de Luxán-Delgado ◽  
Laure Penin-Peyta ◽  
Alba Royo-García ◽  
Beatriz Parejo-Alonso ◽  
...  
Keyword(s):  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Metastatic Potential ◽  
Ductal Adenocarcinoma ◽  
Expression Ratio ◽  
Cytotoxic Effects ◽  
Mitochondrial Homeostasis ◽  
Pancreatic Cancer Cells ◽  
Tumorigenic Potential ◽  
Dose Dependent

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumors, partly due to its intrinsic aggressiveness, metastatic potential, and chemoresistance of the contained cancer stem cells (CSCs). Pancreatic CSCs strongly rely on mitochondrial metabolism to maintain their stemness, therefore representing a putative target for their elimination. Since mitochondrial homeostasis depends on the tightly controlled balance between fusion and fission processes, namely mitochondrial dynamics, we aim to study this mechanism in the context of stemness. In human PDAC tissues, the mitochondrial fission gene DNM1L (DRP1) was overexpressed and positively correlated with the stemness signature. Moreover, we observe that primary human CSCs display smaller mitochondria and a higher DRP1/MFN2 expression ratio, indicating the activation of the mitochondrial fission. Interestingly, treatment with the DRP1 inhibitor mDivi-1 induced dose-dependent apoptosis, especially in CD133+ CSCs, due to the accumulation of dysfunctional mitochondria and the subsequent energy crisis in this subpopulation. Mechanistically, mDivi-1 inhibited stemness-related features, such as self-renewal, tumorigenicity, and invasiveness and chemosensitized the cells to the cytotoxic effects of Gemcitabine. In summary, mitochondrial fission is an essential process for pancreatic CSCs and represents an attractive target for designing novel multimodal treatments that will more efficiently eliminate cells with high tumorigenic potential.

Inhibition of Radiation-Enhanced Expression of Integrin and Metastatic Potential in B16 Melanoma Cells by a Lipoxygenase Inhibitor

1994 ◽  
Vol 140 (3) ◽  
pp. 410 ◽  
Author(s):  
J. M. Onoda ◽  
S. S. Kantak ◽  
M. P. Piechocki ◽  
W. Awad ◽  
R. Chea ◽  
...  
Keyword(s):  
Metastatic Potential ◽  
Melanoma Cells ◽  
B16 Melanoma ◽  
Lipoxygenase Inhibitor ◽  
B16 Melanoma Cells ◽  
Enhanced Expression

scholarly journals THE ROLE AND MECHANISMS OF EPITHELIAL-MESENCHYMAL TRANSITION IN THE PROGRESSION OF MELANOMA

2020 ◽  
Vol 19 (4) ◽  
pp. 8-17
Author(s):  
S. V. Chulkova ◽  
D. A. Ryabchikov ◽  
I. A. Dudina ◽  
I. V. Savchenko ◽  
A. V. Egorova ◽  
...  
Keyword(s):  
Causes Of Death ◽  
Epithelial Mesenchymal Transition ◽  
Deep Understanding ◽  
Metastatic Potential ◽  
Melanoma Cells ◽  
Modern Medicine ◽  
Mesenchymal Transition ◽  
Melanoma Progression ◽  
Leading Role ◽  
Developing Area

Despite the achievements of modern medicine in the diagnosis and treatment of oncological diseases, skin melanoma remains one of the leading causes of death worldwide: every third case of melanoma ends in death. As you know, one of the main causes of death is the high incidence of melanoma progression. It is important to note that the mechanisms of melanoma progression are diverse and the rapidly developing area of drug therapy for tumors requires a deep understanding of their characteristics. This is primarily due to the fact that these processes lead to the formation of special, minor tumor clones with stem properties. They are highly resistant to therapy. The latter is the mainobstacle to effective treatment of melanoma patients. The epithelial-mesenchymal transition (EMT) plays a leading role in the acquisition of metastatic potential by melanoma cells. An important distinguishing feature of EMT is a change in the level of expression of transmembrane glycoproteins involved in cell adhesion. With EMT, both a decrease in the level of E-cadherin and an increase in the expression of N-cadherin are observed. Such a switch in different classes of adhesion molecules leads to the fact that melanoma cells lose contact with neighboring keratinocytes and begin to interact with fibroblasts and endothelial cells. The key regulator in EMT induction in melanoma is the Notch1 signaling pathway, which accelerates N-cadherin expression when activated. In addition, EMT also regulates many other pathways – RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, Wnt/β-catenin, the dysregulation of which is associated with the development of drug resistance in melanoma. The analysis was carried out in the article of modern literature data on the importance of EMT in carcinogenesis and prognosis of melanoma. The modern mechanisms of EMT, currently known prognostic factors, as well as potential therapeutic targets that affect EMT and, accordingly, inhibit the process of metastasis, are described in detail.

Sign in / Sign up

Export Citation Format

Share Document