Notch signaling activation induces cell death in MAPKi‐resistant melanoma cells

Mikheil, Dareen M.; Prabhakar, Kirthana; Arshad, Ayyan; Rodríguez, Carlos; Newton, Michael A.; Setaluri, Vijayasaradhi

doi:10.1111/pcmr.12764

Cited by 10 publications

(5 citation statements)

References 45 publications

(73 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The Notch family receptors are involved in regulating the development, differentiation, and cellular function of multiple cell types [45][46][47][48][49]. In particular, the Notch1 signaling pathway has demonstrated a close relationship with melanoma progression [40,41,[50][51][52][53][54][55]. For example, studies have proven that Notch1 signaling promotes the progression of primary melanoma through activation of mitogen-activated protein kinase/phosphatidylinositol 3-kinase-Akt pathways and upregulation of N-cadherin expression [56].…”

Section: Discussionmentioning

confidence: 99%

Abnormal overexpression of G9a in melanoma cells promotes cancer progression via upregulation of the Notch1 signaling pathway

Jiao

Meng

et al. 2020

Aging

View full text Add to dashboard Cite

Malignant melanoma is a type of very dangerous skin cancer. Histone modifiers usually become dysregulated during the process of carcinoma development, thus there is potential for a histone modifier inhibitor as a useful drug for cancer therapy. There is a multitude of evidence regarding the role of G9a, a histone methyltransferase (HMTase), in tumorigenesis. In this study, we first showed that G9a was significantly upregulated in melanoma patients. Using the TCGA database, we found a significantly higher expression of G9a in primary melanoma samples (n = 461) compared to normal skin samples (n = 551). Next, we knocked down G9a in human M14 and A375 melanoma cell lines in vitro via small interfering RNA (siRNA). This resulted in a significant decrease in cell viability, migration and invasion, and an increase in cell apoptosis. UNC0642 is a small molecule inhibitor of G9a that demonstrates minimal cell toxicity and good in vivo pharmacokinetic characteristics. We investigated the role of UNC0642 in melanoma cells, and detected its anti-cancer effects in vitro and in vivo. Next, we treated cells with UNC0642, and observed a significant decrease in cell viability in M14 and A375 cell lines. Furthermore, treatment with UNC0642 resulted in increased apoptosis. In immunocompetent mice bearing A375 engrafts, treatment with UNC0642 inhibited tumor growth. Results of Western blot analysis revealed that administration of UNC0642 or silencing of G9a expression by siRNA reduced Notch1 expression significantly and decreased the level of Hes1 in A375. All in all, the data from our study demonstrates potential of G9a as a therapeutic target in the treatment of melanoma.

show abstract

Section: Discussionmentioning

confidence: 99%

Abnormal overexpression of G9a in melanoma cells promotes cancer progression via upregulation of the Notch1 signaling pathway

Jiao

Meng

et al. 2020

Aging

View full text Add to dashboard Cite

show abstract

“…We can speculate that the higher expression of RPS6 , TP53 , NOTCH1 and ABL1 observed in regressed melanomas could be associated with a more preserved cell cycle control, apoptosis and proliferation 4,5,6 …”

Section: Total (96) Control Group (50) Regression Group (46) Pmentioning

confidence: 99%

Microenvironment in cutaneous melanomas: a gene expression profile study may explain the role of histological regression

Osella‐Abate

Vignale

Annaratone

et al. 2020

Acad Dermatol Venereol

View full text Add to dashboard Cite

“…Although RBP-J is accepted as the major effector for the canonical Notch, RBP-J independent non-canonical Notch signaling has also reported [17]. Notch signaling is known to contribute to melanoma progression [18], acting both as a tumor promoter or suppressor depending on the cellular context [19][20][21][22]. Mikheil et al showed that forced expression of NICD, the active form of Notch, was sufficient to induce apoptosis independently of MAPK pathway inhibition in melanoma cells, with both intrinsic and acquired resistance to MAPK inhibitors [21].…”

Section: Introductionmentioning

confidence: 99%

“…Notch signaling is known to contribute to melanoma progression [18], acting both as a tumor promoter or suppressor depending on the cellular context [19][20][21][22]. Mikheil et al showed that forced expression of NICD, the active form of Notch, was sufficient to induce apoptosis independently of MAPK pathway inhibition in melanoma cells, with both intrinsic and acquired resistance to MAPK inhibitors [21]. Considering the oncogenic role of Notch1 signaling in melanoma, a phase II trial using broad Notch signaling inhibitors surprisingly only showed minimal clinical activity against metastatic melanoma [19].…”

Section: Introductionmentioning

confidence: 99%

NRN1 interacts with Notch to increase oncogenic STAT3 signaling in melanoma

Devitt,

Westphal,

Pieger

et al. 2024

Cell Commun Signal

View full text Add to dashboard Cite

Background Melanoma is a highly heterogeneous cancer, in which frequent changes in activation of signaling pathways lead to a high adaptability to ever changing tumor microenvironments. The elucidation of cancer specific signaling pathways is of great importance, as demonstrated by the inhibitor of the common BrafV600E mutation PLX4032 in melanoma treatment. We therefore investigated signaling pathways that were influenced by neurotrophin NRN1, which has been shown to be upregulated in melanoma. Methods Using a cell culture model system with an NRN1 overexpression, we investigated the influence of NRN1 on melanoma cells’ functionality and signaling. We employed real time cell analysis and spheroid formation assays, while for investigation of molecular mechanisms we used a kinase phosphorylation kit as well as promotor activity analysis followed by mRNA and protein analysis. Results We revealed that NRN1 interacts directly with the cleaved intracellular domain (NICD) of Notch1 and Notch3, causing a potential retention of NICD in the cytoplasm and thereby reducing the expression of its direct downstream target Hes1. This leads to decreased sequestration of JAK and STAT3 in a Hes1-driven phosphorylation complex. Consequently, our data shows less phosphorylation of STAT3 while presenting an accumulation of total protein levels of STAT3 in association with NRN1 overexpression. The potential of the STAT3 signaling pathway to act in both a tumor suppressive and oncogenic manner led us to investigate specific downstream targets – namely Vegf A, Mdr1, cMet - which were found to be upregulated under oncogenic levels of NRN1. Conclusions In summary, we were able to show that NRN1 links oncogenic signaling events between Notch and STAT3 in melanoma. We also suggest that in future research more attention should be payed to cellular regulation of signaling molecules outside of the classically known phosphorylation events. Graphical Abstract

show abstract

Notch signaling activation induces cell death in MAPKi‐resistant melanoma cells

Cited by 10 publications

References 45 publications

Abnormal overexpression of G9a in melanoma cells promotes cancer progression via upregulation of the Notch1 signaling pathway

Abnormal overexpression of G9a in melanoma cells promotes cancer progression via upregulation of the Notch1 signaling pathway

Microenvironment in cutaneous melanomas: a gene expression profile study may explain the role of histological regression

NRN1 interacts with Notch to increase oncogenic STAT3 signaling in melanoma

Contact Info

Product

Resources

About