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 DGAT1 is a lipid metabolism oncoprotein that enables cancer cells to accumulate fatty acid while avoiding lipotoxicity

2020 ◽  
Author(s):  
Daniel J. Wilcock ◽  
Andrew P. Badrock ◽  
Rhys Owen ◽  
Melissa Guerin ◽  
Andrew D. Southam ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Cell Growth ◽  
Cancer Cells ◽  
Melanoma Cell ◽  
Drug Targets ◽  
Lipid Peroxides ◽  
Acid Oxidation ◽  
Growth Factor Signaling ◽  
Bona Fide

ABSTRACTDysregulated cellular metabolism is a hallmark of cancer. As yet, few druggable oncoproteins directly responsible for this hallmark have been identified. Increased fatty acid acquisition allows cancer cells to meet their membrane biogenesis, ATP, and signaling needs. Excess fatty acids suppress growth factor signaling and cause oxidative stress in non-transformed cells, but surprisingly not in cancer cells. Molecules underlying this cancer adaptation may provide new drug targets. Here, we identify Diacylglycerol O-acyltransferase 1 (DGAT1), an enzyme integral to triacylglyceride synthesis and lipid droplet formation, as a frequently up-regulated oncoprotein allowing cancer cells to tolerate excess fatty acids. DGAT1 over-expression alone induced melanoma in zebrafish melanocytes, and co-operated with oncogenic BRAF or NRAS for more rapid melanoma formation. Mechanistically, DGAT1 stimulated melanoma cell growth through sustaining mTOR kinase–S6 kinase signaling and suppressed cell death by tempering fatty acid oxidation, thereby preventing accumulation of reactive oxygen species including lipid peroxides.SIGNIFICANCEWe show that DGAT1 is a bona fide oncoprotein capable of inducing melanoma formation and co-operating with other known drivers of melanoma. DGAT1 facilitates enhanced fatty acid acquisition by melanoma cells through suppressing lipototoxicity. DGAT1 is also critical for maintaining S6K activity required for melanoma cell growth.

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.

Differential necrophoric behaviour of the ant Solenopsis invicta towards fungal-infected corpses of workers and pupae

2015 ◽  
Vol 105 (5) ◽  
pp. 607-614 ◽  
Author(s):  
H.-L. Qiu ◽  
L.-H. Lu ◽  
Q.-X. Shi ◽  
C.-C. Tu ◽  
T. Lin ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Oleic Acid ◽  
Linoleic Acid ◽  
Palmitic Acid ◽  
Social Insects ◽  
Metarhizium Anisopliae ◽  
Solenopsis Invicta ◽  
Developmental Stages ◽  
Underlying Mechanism ◽  
Refuse Pile

AbstractNecrophoric behaviour is critical sanitation behaviour in social insects. However, little is known about the necrophoric responses of workers towards different developmental stages in a colony as well as its underlying mechanism. Here, we show that Solenopsis invicta workers display distinct necrophoric responses to corpses of workers and pupae. Corpses of workers killed by freezing (dead for <1 h) were carried to a refuse pile, but pupal corpses would take at least 1 day to elicit workers’ necrophoric response. Metarhizium anisopliae-infected pupal corpses accelerated the necrophoric behaviour of resident workers, with 47.5% of unaffected corpses and 73.8% infected corpses discarded by 1 day post-treatment). We found that fungus-infected pupal corpses had a higher concentration of fatty acids (palmitic acid, oleic acid and linoleic acid) on their surface. We experimentally confirmed that linoleic and oleic acids would elicit a necrophoric response in workers. The appearance of linoleic and oleic acids appeared to be chemical signals involved in recognition of pupal corpses, and M. anisopliae infection could promote the accumulation of fatty acids on surface of pupal corpses resulting in accelerated necrophoric responses of workers.

scholarly journals ADT-OH exhibits anti-metastatic activity on malignant melanoma through inhibition of FAK/Paxillin signaling pathways

2020 ◽  
Author(s):  
Fangfang Cai ◽  
Huangru Xu ◽  
Shihui Yu ◽  
Ping Li ◽  
Yanyan Lu ◽  
...  
Keyword(s):  
Wound Healing ◽  
Metastatic Melanoma ◽  
Signaling Pathways ◽  
Underlying Mechanism ◽  
Melanoma Cells ◽  
Tumor Xenograft ◽  
Migration And Invasion ◽  
Adhesive Properties ◽  
B16f10 Cells

Abstract Background: Melanoma is a highly aggressive cancer, and its high metastasis results in a high lethality. Hydrogen sulfide (H2S) is now widely recognized as the third endogenous gas delivery substance and may play a key role in cancer biological processes. The present study was designed to evaluate the anti-metastatic effect of H2S-donor ADT-OH on melanoma cells and the underlying mechanism.Methods: Firstly, the effect of ADT-OH on the migration of melanoma cells was explored in vivo by the mouse footpad injection model and the mouse tail vein metastasis model. Tumor xenograft growth and tumor tissue H&E analyses were also measured in vivo. Then, the migration inhibitory effect and the underlying mechanism of ADT-OH on B16F10, B16F1 and A375 melanoma cell lines were evaluated by wound healing, transwell, western blot and immunofluorescence analyses. Results: Our data showed that ADT-OH inhibited the migration and invasion of melanoma cells significantly in vivo in three different animal models. Further research showed that ADT-OH significantly suppressed the migratory, invasive and adhesive properties of A375 and B16F10 cells as measured by the wound-healing and transwell assays. Mechanistically, ADT-OH treatment suppressed the EMT processes and reduced the enzymatic activity of FAK and Paxillin. Moreover, abnormal CSE/CBS and AKT signaling pathways in A375 and B16F10 cells were notably observed following ADT-OH treatment. Additionally, ADT-OH at higher concentration significantly inhibited the proliferation of highly metastatic melanoma A375 and B16F10 cells.Conclusions: Our results suggest that ADT-OH exerts anti-metastasis activity in melanoma cells by suppressing the EMT process through the CSE/CBS and FAK signaling pathways, and it might be used as an agent against metastatic melanoma in future.

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 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 Effect of fatty acids on melanogenesis and tumor cell growth in melanoma cells

2019 ◽  
Vol 60 (9) ◽  
pp. 1491-1502 ◽  
Author(s):  
Hidetoshi Yamada ◽  
Mayuka Hakozaki ◽  
Aiko Uemura ◽  
Tetsuro Yamashita
Keyword(s):  
Fatty Acids ◽  
Cell Growth ◽  
Tumor Cell ◽  
Melanoma Cells ◽  
Tumor Cell Growth

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.

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