scholarly journals SPRED1 deletion confers resistance to MAPK inhibition in melanoma

2020 ◽  
Vol 218 (3) ◽  
Author(s):  
Julien Ablain ◽  
Sixue Liu ◽  
Gatien Moriceau ◽  
Roger S. Lo ◽  
Leonard I. Zon
Keyword(s):  
Melanoma Cell ◽  
Acquired Resistance ◽  
Human Melanoma ◽  
Functional Evaluation ◽  
Mapk Activity ◽  
Braf Inhibition ◽  
Novel Therapeutic Strategies ◽  
Mutant Braf

Functional evaluation of genetic lesions can discover a role in cancer initiation and progression and help develop novel therapeutic strategies. We previously identified the negative MAPK regulator SPRED1 as a novel tumor suppressor in KIT-driven melanoma. Here, we show that SPRED1 is also frequently deleted in human melanoma driven by mutant BRAF. We found that SPRED1 inactivation in human melanoma cell lines and primary zebrafish melanoma conferred resistance to BRAFV600E inhibition in vitro and in vivo. Mechanistically, SPRED1 loss promoted melanoma cell proliferation under mutant BRAF inhibition by reactivating MAPK activity. Consistently, biallelic deletion of SPRED1 was observed in a patient whose melanoma acquired resistance to MAPK-targeted therapy. These studies combining work in human cells and in vivo modeling in zebrafish demonstrate a new mechanism of resistance to BRAFV600E inhibition in melanoma.

scholarly journals PERK mediates resistance to BRAF inhibition in melanoma with impaired PTEN

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Yifei Qin ◽  
Qiang Zuo ◽  
Lei Huang ◽  
Liping Huang ◽  
Glenn Merlino ◽  
...  
Keyword(s):  
Critical Role ◽  
Acquired Resistance ◽  
Braf Inhibitor ◽  
Treatment Needs ◽  
Braf Inhibition ◽  
Melanoma Treatment ◽  
Pten Inhibition ◽  
Mutant Braf

AbstractTargeting mutant BRAF in patients with melanomas harboring this oncogene has been highly successful as a first-line treatment, but other mutations may affect its efficacy and alter the route of acquired resistance resulting in recurrence and poor prognosis. As an evolving strategy, melanoma treatment needs to be expanded to include targets based on newly discovered emerging molecules and pathways. We here show that PERK plays a critical role in BRAF inhibitor-acquired resistance in melanoma with impaired PTEN. Inhibition of PERK by either shRNA or a pharmacological inhibitor blocked the growth of BRAF inhibitor-resistant melanoma with impaired PTEN in vitro and in vivo, suggesting an effective approach against melanomas with mutant BRAF and PTEN deficiency. Our current findings, along with our previous discovery that the AXL/AKT axis mediates resistance to BRAF inhibition in melanoma with wild-type PTEN, provide new insights toward a strategy for combating BRAF inhibition-acquired resistance in BRAF mutant melanoma with different PTEN statuses.

scholarly journals Nck2 promotes human melanoma cell proliferation, migration and invasion in vitro and primary melanoma-derived tumor growth in vivo

BMC Cancer ◽  
2011 ◽  
Vol 11 (1) ◽  
Author(s):  
Mélissa Labelle-Côté ◽  
Julie Dusseault ◽  
Salma Ismaïl ◽  
Aude Picard-Cloutier ◽  
Peter M Siegel ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Melanoma Cell ◽  
Primary Melanoma ◽  
Human Melanoma ◽  
Human Melanoma Cell ◽  
Migration And Invasion ◽  
Melanoma Cell Proliferation

Luteolin inhibits proliferation and induces apoptosis of human melanoma cells in vivo and in vitro by suppressing MMP-2 and MMP-9 through the PI3K/AKT pathway

2019 ◽  
Vol 10 (2) ◽  
pp. 703-712 ◽  
Author(s):  
Xin Yao ◽  
Wei Jiang ◽  
Danhong Yu ◽  
Zhaowei Yan
Keyword(s):  
Malignant Melanoma ◽  
Incidence Rate ◽  
Melanoma Cell ◽  
Melanoma Cells ◽  
Human Melanoma ◽  
Akt Pathway ◽  
Human Melanoma Cells ◽  
Cell Metastasis

Since the incidence rate of malignant melanoma is increasing annually, development of drugs against melanoma cell metastasis has become more urgent.

scholarly journals SUN-LB27 Interleukin-8 - a Possible Target for Melanoma Treatment? In-Vitro Studies Based on Human Melanoma Cell Models

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Pandurangan Ramaraj
Keyword(s):  
Cell Growth ◽  
Melanoma Cell ◽  
In Vitro Study ◽  
Human Melanoma ◽  
Human Melanoma Cell ◽  
Melanoma Treatment ◽  
Pre Treatment ◽  
Melanoma Growth

Abstract Previous clinical studies showed that menstruating females were better protected in melanoma than post-menopausal women and men of any age. In addition, epidemiological studies showed an increased male mortality in melanoma. But these studies did not correlate with steroid status in females. Our in-vitro study showed female sex hormone progesterone significantly inhibited human melanoma cell growth. Further in-vitro study showed that progesterone action was mediated by a specific suppression of pro-inflammatory cytokine IL-8. Our research also showed that addition of IL-8 (1 ng/ml) to melanoma cells stimulated cell growth (117%) and suppression of IL-8 by curcumin (100 μM) pre-treatment suppressed human melanoma cell growth (26%) in-vitro. This observation prompted us to check the effect of male sex hormones androstenedione (AD) and testosterone (T) on melanoma cell growth. AD and T also suppressed cell growth and IL-8 secretion, but not as significantly as that of progesterone. However, addition of progesterone (10 μM) along with androgens showed an additive effect on the inhibition of melanoma cell growth and suppression of IL-8 secretion. As steroids (P, AD, T) targeted IL-8 for their action, it was decided to check whether vitamin-D3 also targeted IL-8 secretion and cell growth. Active form of vit-D3 (25 μM) also suppressed IL-8 secretion and cell growth. But, addition of progesterone (50 μM) along with D3 significantly suppressed cell growth and IL-8 secretion. This brought IL-8 into focus as a key molecule regulating melanoma cell growth. In order to check whether IL-8 was the molecule involved in regulating melanoma cell growth, IL-8 rescue experiment after curcumin (25 μM) pre-treatment was carried out. IL-8 (100 ng/ml) was able to rescue cell growth completely after pre-treatment with curcumin, suggesting IL-8 was the molecule involved in regulating melanoma cell growth. Literature also suggested important role for IL-8 in regulating melanoma cell growth. Conditional expression of IL-8 in nude mouse by Dr. Singh et al., indicated in-vivo role of IL-8 in melanoma growth and metastasis. Conclusion: Both, in-vitro and in-vivo studies suggested an important role for IL-8 in regulating melanoma growth and metastasis. So, IL-8 could be targeted to arrest melanoma growth and metastasis in-vivo. Hence, IL-8 could be a potential target for melanoma treatment.

scholarly journals Nicotinamide inhibits melanoma in vitro and in vivo

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Francesca Scatozza ◽  
Federica Moschella ◽  
Daniela D’Arcangelo ◽  
Stefania Rossi ◽  
Claudio Tabolacci ◽  
...  
Keyword(s):  
Cell Death ◽  
Melanoma Cell ◽  
In Silico ◽  
Fold Increase ◽  
Human Melanoma ◽  
G1 Phase ◽  
Expression Levels ◽  
Ifn Γ

Abstract Background Even though new therapies are available against melanoma, novel approaches are needed to overcome resistance and high-toxicity issues. In the present study the anti-melanoma activity of Nicotinamide (NAM), the amide form of Niacin, was assessed in vitro and in vivo. Methods Human (A375, SK-MEL-28) and mouse (B16-F10) melanoma cell lines were used for in vitro investigations. Viability, cell-death, cell-cycle distribution, apoptosis, Nicotinamide Adenine Dinucleotide+ (NAD+), Adenosine Triphosphate (ATP), and Reactive Oxygen Species (ROS) levels were measured after NAM treatment. NAM anti-SIRT2 activity was tested in vitro; SIRT2 expression level was investigated by in silico transcriptomic analyses. Melanoma growth in vivo was measured in thirty-five C57BL/6 mice injected subcutaneously with B16-F10 melanoma cells and treated intraperitoneally with NAM. Interferon (IFN)-γ-secreting murine cells were counted with ELISPOT assay. Cytokine/chemokine plasmatic levels were measured by xMAP technology. Niacin receptors expression in human melanoma samples was also investigated by in silico transcriptomic analyses. Results NAM reduced up to 90% melanoma cell number and induced: i) accumulation in G1-phase (40% increase), ii) reduction in S- and G2-phase (about 50% decrease), iii) a 10-fold increase of cell-death and 2.5-fold increase of apoptosis in sub-G1 phase, iv) a significant increase of NAD+, ATP, and ROS levels, v) a strong inhibition of SIRT2 activity in vitro. NAM significantly delayed tumor growth in vivo (p ≤ 0.0005) and improved survival of melanoma-bearing mice (p ≤ 0.0001). About 3-fold increase (p ≤ 0.05) of Interferon-gamma (IFN-γ) producing cells was observed in NAM treated mice. The plasmatic expression levels of 6 cytokines (namely: Interleukin 5 (IL-5), Eotaxin, Interleukin 12 (p40) (IL12(p40)), Interleukin 3 (IL-3), Interleukin 10 (IL-10) and Regulated on Activation Normal T Expressed and Secreted (RANTES) were significantly changed in the blood of NAM treated mice, suggesting a key role of the immune response. The observed inhibitory effect of NAM on SIRT2 enzymatic activity confirmed previous evidence; we show here that SIRT2 expression is significantly increased in melanoma and inversely related to melanoma-patients survival. Finally, we show for the first time that the expression levels of Niacin receptors HCAR2 and HCAR3 is almost abolished in human melanoma samples. Conclusion NAM shows a relevant anti-melanoma activity in vitro and in vivo and is a suitable candidate for further clinical investigations.

scholarly journals An In Vitro-In Vivo Evaluation of the Antiproliferative and Antiangiogenic Effect of Flavone Apigenin against SK-MEL-24 Human Melanoma Cell Line

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Alexandra Ghiƫu ◽  
Ioana Zinuca Pavel ◽  
Stefana Avram ◽  
Brigitta Kis ◽  
Daliana Minda ◽  
...  
Keyword(s):  
Cell Line ◽  
Melanoma Cell ◽  
Melanoma Cell Line ◽  
Human Melanoma ◽  
Human Melanoma Cell Line ◽  
Human Melanoma Cell ◽  
Cell Growth And Migration ◽  
Vitro Effect

One of the most important class of natural compounds with successful preclinical results in the management of cancer is the flavonoids. Due to the plethora of biological activities, apigenin (4 ′ ,5,7 trihydroxyflavone) is a main representant of the flavone subclass. Although the antiproliferative and antiangiogenic effects of apigenin were studied on a significant number of human and murine melanoma cell lines, in order to complete the data existing in the literature, the aim of this study is to evaluate the in vitro effect of apigenin on SK-MEL-24 human melanoma cell line as well as in vivo on tumor angiogenesis using the aforementioned cell line on the chorioallantoic membrane assay. Results have shown that in the range of tested doses, the phytocompound presents significant antiproliferative, cytotoxic, and antimigratory potential at 30 μM, respectively, 60 μM. Moreover, the phytocompound in both tested concentrations limited melanoma cell growth and migration and induced a reduced angiogenic reaction limiting melanoma cell development.

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