scholarly journals CD147 promotes melanoma cell growth via SOX4-mediated glycolytic metabolism

2021 ◽  
Vol 19 (12) ◽  
pp. 2521-2527
Author(s):  
Xiaohui Sun ◽  
Pengfei Yang ◽  
Yuan Jiang
Keyword(s):  
Cell Growth ◽  
Melanoma Cell ◽  
Colony Formation ◽  
Normal Tissue ◽  
High Mobility ◽  
Melanoma Cells ◽  
Cellular Level ◽  
Adjacent Normal Tissue ◽  
Cluster Of Differentiation ◽  
Melanoma Tissue

Purpose: To determine the functional roles of cluster of differentiation 147 (CD147) in glycolysis in melanoma cells.Methods: CD147 expression in melanoma tissue and adjacent normal tissue was determined using quantitative real time polymrase chain reaction (qRT-PCR) and immunohistochemistry. Cell Counting Kit-8 (CCK-8) and colony formation assays were used to evaluate cell viability and colony formation, respectively. The role of CD147 in glycolysis in melanoma cells was investigated by determining glucose uptake, production of lactate, and cellular level of ATP.Results: CD147 was enhanced more in melanoma tissue than that in the adjacent normal tissue (p < 0.001). CD147 overexpression promoted the viability and colony formation of melanoma cells. On the other hand, CD147 silencing decreased the viability and colony formation of melanoma cells. Glucose uptake, production of lactate, and cellular level of ATP were upregulated in melanoma cells by CD147 overexpression and downregulated by shRNA-mediated depletion of CD147. CD147 increased expression of C-X-C motif chemokine ligand 1 (CXCL1) to activate the sex-determining region Y-related high-mobility group box 4 (SOX4) pathway. Knockdown of CXCL1 attenuated the positive regulatory effect of CD147 on SOX4. Besides, overexpression of SOX4 reversed the suppressive effects of CD147 silencing on melanoma cell viability, colony formation, and glycolysis.Conclusion: CD147 contributes to melanoma cell growth via upregulation of SOX-mediated glycolysis, thus providing a therapeutic avenue for the management of melanoma. Keywords: Cluster of differentiation 147, CD147, Sex-determining region Y-related high-mobility group box 4, Melanoma, Cell growth, Glycolysis

scholarly journals Cinobufagin Suppresses Melanoma Cell Growth by Inhibiting LEF1

2020 ◽  
Vol 21 (18) ◽  
pp. 6706
Author(s):  
Geon-Hee Kim ◽  
Xue-Quan Fang ◽  
Woo-Jin Lim ◽  
Jooho Park ◽  
Tae-Bong Kang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Growth ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Melanoma Cell ◽  
Transcriptional Activity ◽  
Melanoma Cells ◽  
Lung Cancer Cells ◽  
Luciferase Assay ◽  
Dependent Manner

Constitutive activation of the β-catenin dependent canonical Wnt signaling pathway, which enhances tumor growth and progression in multiple types of cancer, is commonly observed in melanoma. LEF1 activates β-catenin/TCF4 transcriptional activity, promoting tumor growth and progression. Although several reports have shown that LEF1 is highly expressed in melanoma, the functional role of LEF1 in melanoma growth is not fully understood. While A375, A2058, and G361 melanoma cells exhibit abnormally high LEF1 expression, lung cancer cells express lower LEF1 levels. A luciferase assay-based high throughput screening (HTS) with a natural compound library showed that cinobufagin suppressed β-catenin/TCF4 transcriptional activity by inhibiting LEF1 expression. Cinobufagin decreases LEF1 expression in a dose-dependent manner and Wnt/β-catenin target genes such as Axin-2, cyclin D1, and c-Myc in melanoma cell lines. Cinobufagin sensitively attenuates cell viability and induces apoptosis in LEF1 expressing melanoma cells compared to LEF1-low expressing lung cancer cells. In addition, ectopic LEF1 expression is sufficient to attenuate cinobufagin-induced apoptosis and cell growth retardation in melanoma cells. Thus, we suggest that cinobufagin is a potential anti-melanoma drug that suppresses tumor-promoting Wnt/β-catenin signaling via LEF1 inhibition.

Temozolomide combined with the PI3K inhibitor LY294002 or the mTOR inhibitor rapamycin inhibits melanoma cell growth, survival and invasion

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8559-8559 ◽  
Author(s):  
F. E. Meier ◽  
K. Lasithiotakis ◽  
B. Schittek ◽  
T. Sinnberg ◽  
C. Garbe
Keyword(s):  
Cell Growth ◽  
Metastatic Melanoma ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Melanoma Cell ◽  
Mtor Inhibitor ◽  
Melanoma Cells ◽  
Mapk Signaling ◽  
Pi3k Inhibitor ◽  
Mapk Signaling Pathways

8559 Background: Potential therapeutic targets in the treatment of metastatic melanoma have emerged, to which pharmacological inhibitors have been designed, which may enhance tumor chemosensitivity. In melanoma, dacarbazine is considered to be the most effective agent although total responses do not exceed 20% The clinical activity of temozolomide is similar to that of dacarbazine, but temozolomide has the advantages of being absorbed orally and of crossing the blood-brain barrier. Many clinical trials of targeted therapy and chemotherapy combinations lack rigorous preclinical evaluation and may neglect relevant mechanistic interactions. The PI3K-AKT-mTOR (AKT) and RAS-RAF- MEK-ERK (MAPK) signaling pathways are constitutively activated in melanoma, and appear to play a role in chemoresistance. Methods: In this study, a panel of pharmacological inhibitors was utilized in order to block the AKT and MAPK signaling pathways at different levels (AKT: PI3K, mTOR; MAPK: RAF, MEK) in 5 human metastatic melanoma cell lines. The effects on chemosensitivity to temozolomide and cisplatin was then investigated. Results: The effects of most inhibitors on chemosensitivity varied significantly between the different cell lines. However, LY294002, a PI3K inhibitor and rapamycin, an mTOR inhibitor, consistently enhanced chemosensitivity. Treatment of melanoma cells with temozolomide or cisplatin combined with LY294002 or rapamycin had a strong effect on melanoma cell growth and survival. Invasive melanoma growth in organotypic cultures of human skin was suppressed completely. The most pronounced potentiation of efficacy was seen with temozolomide in combination with rapamycin. Conclusions: These data suggest that LY294002 and rapamycin can render melanoma cells susceptible to apoptosis, induced by chemotherapeutic agents such as temozolomide and cisplatin. Since both temozolomide and rapamycin are used clinically, the combination of temozolomide with rapamycin might potentially be utilized as an approach in melanoma treatment. This combination merits clinical investigation. No significant financial relationships to disclose.

scholarly journals Subcutaneous Adipocytes Promote Melanoma Cell Growth by Activating the Akt Signaling Pathway

2014 ◽  
Vol 289 (44) ◽  
pp. 30525-30537 ◽  
Author(s):  
Hiu Yee Kwan ◽  
Xiuqiong Fu ◽  
Bin Liu ◽  
Xiaojuan Chao ◽  
Chi Leung Chan ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Cell Growth ◽  
Palmitic Acid ◽  
Melanoma Cell ◽  
Underlying Mechanism ◽  
Melanoma Cells ◽  
Cell Cycle Distribution ◽  
Tensin Homolog ◽  
B16f10 Cells ◽  
Isolated Adipocytes

Tumorigenesis involves constant communication between tumor cells and neighboring normal cells such as adipocytes. The canonical function of adipocytes is to store triglyceride and release fatty acids for other tissues. This study was aimed to find out if adipocytes promoted melanoma cell growth and to investigate the underlying mechanism. Here we isolated adipocytes from inguinal adipose tissue in mice and co-cultured with melanoma cells. We found that the co-cultured melanoma had higher lipid accumulation compared with mono-cultured melanoma. In addition, fluorescently labeled fatty acid BODIPY® FLC16 signal was detected in melanoma co-cultured with the adipocytes that had been loaded with the fluorescent dye, suggesting that the adipocytes provide fatty acids to melanoma cells. Compared with mono-cultured melanoma, co-cultured melanoma cells had a higher proliferation and phospho-Akt (Ser-473 and Thr-450) expression. Overexpression of Akt mutants in melanoma cells reduced the co-culture-enhanced proliferation. A lipidomic study showed that the co-cultured melanoma had an elevated palmitic acid level. Interestingly, we found that palmitic acid stimulated melanoma cell proliferation, changed the cell cycle distribution, and increased phospho-Akt (Ser-473 and Thr-450) and PI3K but not phospho-PTEN (phosphophosphatase and tensin homolog) expressions. More importantly, the palmitic acid-stimulated proliferation was further enhanced in the Akt-overexpressed melanoma cells and was reduced by LY294002 or knockdown of endogenous Akt or overexpression of Akt mutants. We also found that palmitic acid-pretreated B16F10 cells were grown to a significantly larger tumor in mice compared with control cells. Taken together, we suggest that adipocytes may serve as an exogenous source of palmitic acid that promotes melanoma cell growth by activating Akt.

scholarly journals Inhibitory Effects of Trehalose on Malignant Melanoma Cell Growth: Implications for a Novel Topical Anticancer Agent on the Ocular Surface

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Takashi Kudo ◽  
Kimio Takeuchi ◽  
Yu-ichi Ebina ◽  
Mitsuru Nakazawa
Keyword(s):  
Cell Cycle ◽  
Flow Cytometry ◽  
Cell Growth ◽  
Malignant Melanoma ◽  
Melanoma Cell ◽  
Ocular Surface ◽  
Melanoma Cells ◽  
Apoptotic Cells ◽  
Inhibitory Effects ◽  
Malignant Melanoma Cell

Purpose. To investigate the inhibitory effects of trehalose on malignant melanoma cell growth. Methods. We cultured human malignant melanoma cells in a medium containing trehalose (control/2.5%/5.0%/7.5%/10.0%) and used the MTT assay to evaluate the growth activities. Subsequently, trehalose was topically instilled on subconjunctivally inoculated melanoma cells in F334/NJcl-rmu/rmu rats, followed by a histopathological evaluation of tumor growth. Using flow cytometry, we compared the distribution of the cell cycle, rate of apoptotic cells, and intracellular factors related to the cell cycle in cultured melanoma cells after trehalose treatment. Results. The MTT study showed that proliferation of melanoma cells was significantly inhibited by ≧ 5% of trehalose concentrations in the culture media. Subconjunctivally inoculated melanoma cell masses were significantly smaller in eyes administered trehalose as compared to controls. Flow cytometry analyses demonstrated that the trehalose groups had increased rates of G2/M phase cells and apoptotic cells in the cell culture. These cells also exhibited increased expressions of cell-cycle inhibitory factors. Conclusions. The current results show trehalose inhibits malignant melanoma cell growth by inducing G2/M cell cycle arrest and apoptosis, suggesting trehalose as a potential candidate for a topical agent to inhibit proliferation of malignant tumor cells of the ocular surface.

scholarly journals E3 ubiquitin ligase PARK2, an inhibitor of melanoma cell growth, is repressed by the oncogenic ERK1/2-ELK1 transcriptional axis

2020 ◽  
Vol 295 (47) ◽  
pp. 16058-16071
Author(s):  
Valentina Montagnani ◽  
Luisa Maresca ◽  
Alessandro Apollo ◽  
Sara Pepe ◽  
Ryan M. Carr ◽  
...  
Keyword(s):  
Cell Growth ◽  
Malignant Melanoma ◽  
Melanoma Cell ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Melanoma Cells ◽  
Mapk Signaling ◽  
Braf V600e ◽  
Promising Therapeutic Approach ◽  
Melanoma Growth

Malignant melanoma, the most aggressive form of skin cancer, is characterized by high prevalence of BRAF/NRAS mutations and hyperactivation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), mitogen-activated protein kinases (MAPK), leading to uncontrolled melanoma growth. Efficacy of current targeted therapies against mutant BRAF or MEK1/2 have been hindered by existence of innate or development of acquired resistance. Therefore, a better understanding of the mechanisms controlled by MAPK pathway driving melanogenesis will help develop new treatment approaches targeting this oncogenic cascade. Here, we identify E3 ubiquitin ligase PARK2 as a direct target of ELK1, a known transcriptional effector of MAPK signaling in melanoma cells. We show that pharmacological inhibition of BRAF-V600E or ERK1/2 in melanoma cells increases PARK2 expression. PARK2 overexpression reduces melanoma cell growth in vitro and in vivo and induces apoptosis. Conversely, its genetic silencing increases melanoma cell proliferation and reduces cell death. Further, we demonstrate that ELK1 is required by the BRAF-ERK1/2 pathway to repress PARK2 expression and promoter activity in melanoma cells. Clinically, PARK2 is highly expressed in WT BRAF and NRAS melanomas, but it is expressed at low levels in melanomas carrying BRAF/NRAS mutations. Overall, our data provide new insights into the tumor suppressive role of PARK2 in malignant melanoma and uncover a novel mechanism for the negative regulation of PARK2 via the ERK1/2-ELK1 axis. These findings suggest that reactivation of PARK2 may be a promising therapeutic approach to counteract melanoma growth.

scholarly journals A Review of Progesterone Effects on Human Melanoma Cell Growth In-Vitro

2021 ◽  
Author(s):  
Pandurangan Ramaraj
Keyword(s):  
Cell Growth ◽  
Steroid Hormones ◽  
Melanoma Cell ◽  
Clinical Studies ◽  
Melanoma Cells ◽  
Human Melanoma ◽  
Human Melanoma Cell ◽  
And Migration ◽  
Post Menopausal

Progesterone, a female sex hormone not only has a role in reproduction, but also in protecting females in melanoma. A survey of steroid hormones actions steroid hormones actions survey on melanoma cells and literature survey showed that progesterone inhibited mouse and human melanoma cell growth significantly in-vitro. Progesterone not only inhibited cell growth, but also affected adhesion and migration functions (essential for metastasis) in-vitro. This observation correlated with the clinical studies where they had shown showed an increased survival and delayed metastasis in menstruating females in melanoma. Further, progesterone level in menstruating females (1000–1500 ng/dL) compared to post-menopausal females (20–100 ng/dL) also correlated with previous clinical studies. Progesterone action on melanoma cells, as reported by other researchers also supported the findings from this lab. Hence, progesterone could be the steroid hormone protecting menstruating females in melanoma. Moreover, our recent studies showed that progesterone suppressed pro-inflammatory cytokine IL-8 secretion by the melanoma cells, which decreased melanoma cell growth in-vitro. Hence, progesterone apart from reproductive function may also be involved in protecting menstruating females in melanoma.

scholarly journals Low Molecular Weight Components in Aqueous Echinacea Purpurea Leaf Extract Inhibit Melanoma Cell Growth

2016 ◽  
Vol 2 (1) ◽  
Author(s):  
Ariel C Yin ◽  
Karina H Goldberg ◽  
Archana Mupparapu ◽  
Edward P Retzbach ◽  
Kingsley Yin ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Cell Growth ◽  
Melanoma Cell ◽  
High Mortality ◽  
Leaf Extract ◽  
Kinase Activity ◽  
Echinacea Purpurea ◽  
Melanoma Cells ◽  
Low Molecular Weight ◽  
Low Molecular Weight Compounds

Melanoma is a skin cancer associated with high mortality. The three year survival rate from advanced melanoma is between 10-15%. One reason for this high mortality rate is that melanoma cells are resistant to traditional chemotherapeutics. Echinacea is a plant genus native to North America with putative anticancer properties. Here, we examined effects of aqueous Echinacea purpurea leaf extract on the growth of melanoma cells and nontransformed fibroblasts. This aqueous extract reduced B16 mouse melanoma cell growth at concentrations that did not inhibit the growth of nontransformed NIH3T3 fibroblasts, suggesting that the extract had biological specificity against transformed cells. We also examined the effect of different fractions of the extract on melanoma cell growth. These data indicate that components less than 3 kD in size exhibited the greatest inhibitory action on melanoma cell growth. In addition, these data indicated that larger components in the extract ameliorate the ability of these low molecular weight compounds to inhibit melanoma cell growth. Furthermore, Echinacea extract inhibited the growth of v-Src transformed LA25 cells without reducing Src kinase activity. Taken together, these results suggest that aqueous Echinacea purpurea extract contains low molecular weight compounds that preferentially inhibit tumor cell growth in the face of oncogenic tyrosine kinase activity. These data suggest future studies to better define bioactive compounds in Echinacea purpurea and evaluate their therapeutic efficacy in vivo.

scholarly journals A carbazole compound, 9-ethyl-9H-carbazole-3-carbaldehyde, plays an antitumor function through reactivation of the p53 pathway in human melanoma cells

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Jie Wen ◽  
Wenqian Chen ◽  
Baoxiang Zhao ◽  
Qiuping Xu ◽  
Chang Liu ◽  
...  
Keyword(s):  
Cell Growth ◽  
Growth Inhibition ◽  
P38 Mapk ◽  
Melanoma Cell ◽  
Cell Apoptosis ◽  
Melanoma Cells ◽  
Wild Type ◽  
Carbazole Derivative ◽  
Normal Human ◽  
Melanoma Therapy

Abstractp53, the major tumor suppressor, is frequently mutated in many cancers, and up to 84% of human melanomas harbor wild-type p53, which is considered to be an ideal target for melanoma therapy. Here, we evaluated the antitumor activity of a carbazole derivative, 9-ethyl-9H-carbazole-3-carbaldehyde (ECCA), on melanoma cells. ECCA had a selectively strong inhibitory activity against the growth of BRAF-mutated and BRAF-wild-type melanoma cells but had little effect on normal human primary melanocytes. ECCA inhibited melanoma cell growth by increasing cell apoptosis, which was associated with the upregulation of caspase activities and was significantly abrogated by the addition of a caspase inhibitor. In vivo assays confirmed that ECCA suppressed melanoma growth by enhancing cell apoptosis and reducing cell proliferation, and importantly ECCA did not have any evident toxic effects on normal tissues. RNA-Seq analysis identified several pathways related to cell apoptosis that were affected by ECCA, notably, activation of the p53 signaling pathway. Biochemical assays demonstrated that ECCA enhanced the phosphorylation of p53 at Ser15 in melanoma cells harboring wild-type p53, and importantly, the knockdown or deletion of p53 in those cells counteracted the ECCA-induced apoptosis, as well as senescence. Further investigations revealed that ECCA enhanced the phosphorylation of p38-MAPK and c-Jun N-terminal kinase (JNK), and treatment with either a p38-MAPK or a JNK inhibitor rescued the cell growth inhibition elicited by ECCA, which depended on the expression of the p53 gene. Finally, the combination of ECCA with a BRAF inhibitor significantly enhanced the growth inhibition of melanoma cells. In summary, our study demonstrates that the carbazole derivative, ECCA, induces melanoma cell apoptosis and senescence through the activation of p53 to significantly and selectively suppress the growth of melanoma cells without affecting normal human melanocytes, suggesting its potential to develop a new drug for melanoma therapy.

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