MITF in Normal Melanocytes, Cutaneous and Uveal Melanoma: A Delicate Balance

Gelmi, Maria Chiara; Houtzagers, Laurien E.; Strub, Thomas; Krossa, Imène; Jager, Martine J.

doi:10.3390/ijms23116001

Cited by 39 publications

(27 citation statements)

References 186 publications

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“…In agreement with the MITF expression levels, two main groups of MM cells have been identified: a high-MITF-expression (MITF-high) group with a high proliferation rate and low invasive potential and a low-MITF-expression (MITF-low) group with a low proliferation rate and high invasive potential [31]. Since both MITF-low cells and MITFhigh cells can be mixed within tumors [32,33], it is thought that the phenotypes of these two groups of cells can be switched to fluctuate their proliferative or invasive efficacies without genetic alteration [32,34].…”

Section: Discussionsupporting

confidence: 58%

Significant and Various Effects of ML329-Induced MITF Suppression in the Melanoma Cell Line

Nishikiori,

Watanabe,

Sato

et al. 2024

Cancers

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To study the inhibitory effects on microphthalmia-associated transcription factor (MITF)-related biological aspects in malignant melanomas (MMs) in the presence or absence of the low-molecular MITF specific inhibitor ML329, cell viability, cellular metabolic functions, and three-dimensional (3D) spheroid formation efficacy were compared among MM cell lines including SK-mel-24, A375, dabrafenib- and trametinib-resistant A375 (A375DT), and WM266-4. Upon exposure to 2 or 10 μM of ML329, cell viability was significantly decreased in WM266-4, SK-mel-24, and A375DT cells, but not A375 cells, in a dose-dependent manner, and these toxic effects of ML329 were most evident in WM266-4 cells. Extracellular flux assays conducted using a Seahorse bioanalyzer revealed that treatment with ML329 increased basal respiration, ATP-linked respiration, proton leakage, and non-mitochondrial respiration in WM266-4 cells and decreased glycolytic function in SK-mel-24 cells, whereas there were no marked effects of ML329 on A375 and A375DT cells. A glycolytic stress assay under conditions of high glucose concentrations also demonstrated that the inhibitory effect of ML329 on the glycolytic function of WM266-4 cells was dose-dependent. In addition, ML329 significantly decreased 3D-spheroid-forming ability, though the effects of ML329 were variable among the MM cell lines. Furthermore, the mRNA expression levels of selected genes, including STAT3 as a possible regulator of 3D spheroid formation, KRAS and SOX2 as oncogenic-signaling-related factors, PCG1a as the main regulator of mitochondrial biogenesis, and HIF1a as a major hypoxia transcriptional regulator, fluctuated among the MM cell lines, possibly supporting the diverse ML329 effects mentioned above. The findings of diverse ML329 effects on various MM cell lines suggest that MITF-associated biological activities are different among various types of MM.

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Section: Discussionsupporting

confidence: 58%

Significant and Various Effects of ML329-Induced MITF Suppression in the Melanoma Cell Line

Nishikiori,

Watanabe,

Sato

et al. 2024

Cancers

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“…It is well known that the transcriptional activity of MITF is influenced by its post‐translational modifications and the availability of cooperating partners, including ERK. Of note, MITF activity at the tyrosinase promoter is enhanced by phosphorylation mediated by ERK1/2 at Ser73 [38–40]. Our findings provide novel evidence regarding the relationship between PTX‐induced melanogenesis and the activation of the MITF pathway.…”

Section: Discussionmentioning

confidence: 73%

Paclitaxel alters melanogenesis and causes pigmentation in the skin of gynecological cancer patients

Montero

Sanz

Pérez-Fidalgo

et al. 2023

Fundamemntal Clinical Pharma

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BackgroundPaclitaxel (PTX) is a microtubule‐stabilizing antineoplastic that has been shown to damage healthy tissues like the skin. Hyperpigmentation can be found among the adverse effects caused by PTX, but the literature is limited and the mechanisms driving PTX‐induced pigmentary alterations are unknown.ObjectivesThis study aimed to describe the pigmentary alterations caused by PTX and to determine the effects of PTX on melanocytes.MethodsPigmentary skin alterations were measured in 20 gynecological cancer patients under PTX treatment by using specific probes, which determine the melanin index and the pigmentation level. Melanocytes were incubated with paclitaxel to analyze melanogenesis markers gene expression, melanin content, and transcription factors activation.ResultsPaclitaxel induced alterations in the skin pigmentation with no visible clinical manifestations. Gynecological cancer patients under paclitaxel treatment had an increase in the melanin index and pigmentation levels. In vitro, PTX exposure to melanocytes increased the expression of melanogenesis markers, melanin content, and induced activation of ERK and MITF.ConclusionsThe results suggest that PTX alters pigmentation in patients with no clinically visible manifestations, and these alterations might be driven by its capacity to stimulate melanogenesis on melanocytes through the MITF activation pathway.

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“…BRAF-mutated melanoma tends to belong to MITF-low subgroup [ 93 ]. MITF is a regulator of melanocyte development/survival and melanin synthesis [ 135 ]. It inhibits invasion, inflammation, and EMT.…”

Section: Combination Strategiesmentioning

confidence: 99%

Stem Cell Origin of Cancer: Clinical Implications beyond Immunotherapy for Drug versus Therapy Development in Cancer Care

Tu,

Trikannad,

Vellanki

et al. 2024

Cancers

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Although immunotherapy has revolutionized cancer care, there is still an urgent need to enhance its efficacy and ensure its safety. A correct cancer theory and proper scientific method empower pertinent cancer research and enable effective and efficient drug versus therapy development for patient care. In this perspective, we revisit the concept of immune privilege in a cancer cell versus normal cell, as well as in a cancer stem cell versus normal stem cell. We re-examine whether effective immunotherapies are efficacious due to their anti-cancer and/or immune modulatory mechanisms. We reassess why checkpoint inhibitors (CPIs) are not equal. We reconsider whether one can attribute the utility of immunotherapy to specific cancer subtypes and its futility to certain tumor/immune compartments, components, and microenvironments. We propose ways and means to advance immunotherapy beyond CPIs by combining anti-PD1/L1 with various other treatment modalities according to an appropriate scientific theory, e.g., stem cell origin of cancer, and based on available clinical evidence, e.g., randomized clinical trials. We predict that a stem cell theory of cancer will facilitate the design of better and safer immunotherapy with improved selection of its use for the right patient with the right cancer type at the right time to optimize clinical benefits and minimize potential toxic effects and complications.

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MITF in Normal Melanocytes, Cutaneous and Uveal Melanoma: A Delicate Balance

Cited by 39 publications

References 186 publications

Significant and Various Effects of ML329-Induced MITF Suppression in the Melanoma Cell Line

Significant and Various Effects of ML329-Induced MITF Suppression in the Melanoma Cell Line

Paclitaxel alters melanogenesis and causes pigmentation in the skin of gynecological cancer patients

Stem Cell Origin of Cancer: Clinical Implications beyond Immunotherapy for Drug versus Therapy Development in Cancer Care

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