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

The Notch signaling pathway plays a key role in proliferation and differentiation. We investigated the effect of Jagged 1 (Jag1)-mediated Notch signaling activation in the human limbal stem/progenitor cell (LSC) population and the stratification of the limbal epithelium in vitro. After Notch signaling activation, there was a reduction in the amount of the stem/progenitor cell population, epithelial stratification, and expression of proliferation markers. There was also an increase of the corneal epithelial differentiation. In the presence of Jag1, asymmetric divisions were decreased, and the expression pattern of the polarity protein Par3, normally present at the apical-lateral membrane of basal cells, was dispersed in the cells. We propose a mechanism in which Notch activation by Jag1 decreases p63 expression at the basal layer, which in turn reduces stratification by decreasing the number of asymmetric divisions and increases differentiation.

Download Full-text

Ca2+ overload- and ROS-associated mitochondrial dysfunction contributes to δ-tocotrienol-mediated paraptosis in melanoma cells

APOPTOSIS ◽

10.1007/s10495-021-01668-y ◽

2021 ◽

Author(s):

Michela Raimondi ◽

Fabrizio Fontana ◽

Monica Marzagalli ◽

Matteo Audano ◽

Giangiacomo Beretta ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Mitochondrial Dysfunction ◽

Atp Synthesis ◽

Melanoma Cells ◽

Human Melanoma ◽

Ros Generation ◽

Therapy Outcomes ◽

Human Melanoma Cells ◽

Oxphos Complex

Abstract Melanoma is an aggressive tumor with still poor therapy outcomes. δ-tocotrienol (δ-TT) is a vitamin E derivative displaying potent anti-cancer properties. Previously, we demonstrated that δ-TT triggers apoptosis in human melanoma cells. Here, we investigated whether it might also activate paraptosis, a non-canonical programmed cell death. In accordance with the main paraptotic features, δ-TT was shown to promote cytoplasmic vacuolization, associated with endoplasmic reticulum/mitochondrial dilation and protein synthesis, as well as MAPK activation in A375 and BLM cell lines. Moreover, treated cells exhibited a significant reduced expression of OXPHOS complex I and a marked decrease in oxygen consumption and mitochondrial membrane potential, culminating in decreased ATP synthesis and AMPK phosphorylation. This mitochondrial dysfunction resulted in ROS overproduction, found to be responsible for paraptosis induction. Additionally, δ-TT caused Ca2+ homeostasis disruption, with endoplasmic reticulum-derived ions accumulating in mitochondria and activating the paraptotic signaling. Interestingly, by using both IP3R and VDAC inhibitors, a close cause-effect relationship between mitochondrial Ca2+ overload and ROS generation was evidenced. Collectively, these results provide novel insights into δ-TT anti-melanoma activity, highlighting its ability to induce mitochondrial dysfunction-mediated paraptosis. Graphic Abstract δ-tocotrienol induces paraptotic cell death in human melanoma cells, causing endoplasmic reticulum dilation and mitochondrial swelling. These alterations induce an impairment of mitochondrial function, ROS production and calcium overload.

Download Full-text

CSIG-13. TRPM7 INDUCES TUMORIGENESIS AND STEMNESS THROUGH NOTCH ACTIVATION IN GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa215.125 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii30-ii30

Author(s):

Jingwei Wan ◽

Alyssa Guo ◽

Mingli Liu

Keyword(s):

Notch Signaling ◽

Glioma Cell ◽

Glioma Cells ◽

Inhibitory Effect ◽

Notch Signaling Pathway ◽

Normal Brain ◽

Diffuse Astrocytoma ◽

Notch1 Signaling ◽

Signaling Activation ◽

Proliferation And Invasion

Abstract Our group found that the inhibitory effect of TRPM7 on proliferation and invasion of human glioma cell is mediated by multiple mechanisms. TRPM7 regulates miR-28-5p expression, which suppresses cell proliferation and invasion in glioma cells by targeting Ras-related protein Rap1b. In particular, our group found that TRPM7 channels regulate glioma stem cell (GSC) growth/proliferation through STAT3 and Notch signaling. However, which Notch component(s) is crucial for its activity regulated by TRPM7, and its relationship with other GSC markers, such as CD133 and ALDH1, remain unclear. In the current project, we elucidate the mechanisms of TRMP7’s regulation of Notch signaling pathway that contribute to the development and progression of glioma and maintenance of self-renewal and tumorigenicity of GSC using multiple glioma cell lines (GC) with different molecular subtypes and GSCs derived from the GC lines. 1) We first analyzed TRPM7 expression using the Oncomine database (https://www.oncomine.org) and found that the TRPM7 mRNA expression is significantly increased in anaplastic astrocytoma, diffuse astrocytoma, and GBM patients compared to that in normal brain tissue controls. 2) TRPM7 is expressed in GBM, and its channel activity is correlated with Notch1 activation. Inhibition of TRPM7 downregulates Notch1 signaling, while upregulation of TRPM7 upregulates Notch1 signaling. 3) GSC markers, CD133 and ALDH1, are correlated with TRPM7 in GBM. 4) Targeting TRPM7 suppresses the growth and proliferation of glioma cells through G1/S arrests and apoptosis of glioma cells. 5) Targeting Notch1 suppresses the TRPM7-induced growth and proliferation of glioma cells, as well as the expression of GSC markers CD133 and ALDH1. In summary, TRPM7 is responsible for sustained Notch signaling activation, enhanced expression of GSC markers, and regulation of glioma stemness, which contribute to malignant glioma cell growth and invasion. Notch1 and ligand DII4 are key components that contribute GSC stemness.

Download Full-text

Antitumor and apoptotic effects of quercetin on human melanoma cells involving JNK/P38 MAPK signaling activation

European Journal of Pharmacology ◽

10.1016/j.ejphar.2019.172568 ◽

2019 ◽

Vol 860 ◽

pp. 172568 ◽

Cited By ~ 12

Author(s):

Sung-Hyun Kim ◽

Eun-Seon Yoo ◽

Joong-Seok Woo ◽

So-Hee Han ◽

Jae-Han Lee ◽

...

Keyword(s):

P38 Mapk ◽

Melanoma Cells ◽

Mapk Signaling ◽

Human Melanoma ◽

Human Melanoma Cells ◽

Signaling Activation ◽

Apoptotic Effects

Download Full-text

BH3-mimetic gossypol-induced autophagic cell death in mutant BRAF melanoma cells with high expression of p21Cip1

Life Sciences ◽

10.1016/j.lfs.2014.02.036 ◽

2014 ◽

Vol 102 (1) ◽

pp. 41-48 ◽

Cited By ~ 11

Author(s):

Gun-Hee Jang ◽

Michael Lee

Keyword(s):

Cell Death ◽

Melanoma Cells ◽

Autophagic Cell Death ◽

High Expression ◽

Braf Melanoma ◽

Mutant Braf ◽

Bh3 Mimetic

Download Full-text

Dual Photothermal/Chemotherapy of Melanoma Cells with Albumin Nanoparticles Carrying Indocyanine Green and Doxorubicin Leads to Immunogenic Cell Death

Macromolecular Bioscience ◽

10.1002/mabi.202100353 ◽

2021 ◽

pp. 2100353

Author(s):

Niloofar Heshmati Aghda ◽

Susana Torres Hurtado ◽

Shahad M. Abdulsahib ◽

Emilio J. Lara ◽

James W. Tunnell ◽

...

Keyword(s):

Cell Death ◽

Indocyanine Green ◽

Melanoma Cells ◽

Immunogenic Cell Death ◽

Albumin Nanoparticles

Download Full-text

Methylene blue and photodynamic therapy for melanomas: Inducing different rates of cell death (necrosis and apoptosis) in B16-F10 melanoma cells according to methylene blue concentration and energy dose

Photodiagnosis and Photodynamic Therapy ◽

10.1016/j.pdpdt.2021.102635 ◽

2021 ◽

pp. 102635

Author(s):

Murilo Penteado Del Grande ◽

Andréa Midory Miyake ◽

Márcia Kazumi Nagamine ◽

João Vitor Pereira Leite ◽

Ivone Izabel Mackowiak da Fonseca ◽

...

Keyword(s):

Methylene Blue ◽

Cell Death ◽

Photodynamic Therapy ◽

Melanoma Cells ◽

Energy Dose

Download Full-text

A Novel Fast Photothermal Therapy Using Hot Spots of Gold Nanorods for Malignant Melanoma Cells

Nanomaterials ◽

10.3390/nano8110880 ◽

2018 ◽

Vol 8 (11) ◽

pp. 880 ◽

Cited By ~ 3

Author(s):

Yanhua Yao ◽

Nannan Zhang ◽

Xiao Liu ◽

Qiaofeng Dai ◽

Haiying Liu ◽

...

Keyword(s):

Cell Death ◽

Malignant Melanoma ◽

Gold Nanorods ◽

Plasmon Resonance ◽

Photothermal Therapy ◽

Treatment Time ◽

High Energy ◽

Melanoma Cells ◽

Photothermal Effect ◽

A375 Cells

In this paper, the plasmon resonance effects of gold nanorods was used to achieve rapid photothermal therapy for malignant melanoma cells (A375 cells). After incubation with A375 cells for 24 h, gold nanorods were taken up by the cells and gold nanorod clusters were formed naturally in the organelles of A375 cells. After analyzing the angle and space between the nanorods in clusters, a series of numerical simulations were performed and the results show that the plasmon resonance coupling between the gold nanorods can lead to a field enhancement of up to 60 times. Such high energy localization causes the temperature around the nanorods to rise rapidly and induce cell death. In this treatment, a laser as low as 9.3 mW was used to irradiate a single cell for 20 s and the cell died two h later. The cell death time can also be controlled by changing the power of laser which is focused on the cells. The advantage of this therapy is low laser treatment power, short treatment time, and small treatment range. As a result, the damage of the normal tissue by the photothermal effect can be greatly avoided.

Download Full-text