Ceramide channels: destabilization by Bcl-xL and role in apoptosis

Chang, Kai-Ti; Anishkin, Andriy; Patwardhan, Gauri A.; Beverly, Levi J.; Siskind, Leah J.; Colombini, Marco

doi:10.1016/j.bbamem.2015.07.013

Cited by 50 publications

(34 citation statements)

References 55 publications

(85 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Prior work by several labs identified abnormal cell death as causative for NTDs . Therefore, it was important to determine whether exposure to C2 during development increased apoptotic activity within the neural tube.…”

Section: Discussionmentioning

confidence: 99%

Ceramide: a novel inducer for neural tube defects

Ross

Piorczynski

Harvey

et al. 2019

Developmental Dynamics

View full text Add to dashboard Cite

Background Circulating plasma ceramides, a class of bioactive sphingolipids, are elevated in metabolic disorders, including obesity. Infants of women with these disorders are at 2‐ to 3‐fold greater risk for developing a neural tube defect (NTD). This study aimed to test the effects of embryonic exposure to C2‐ceramides (C2) during neural tube closure. Preliminary data shows an increase in NTDs in chick embryos after C2 exposure, and addresses potential mechanisms. Results Cell and embryo models were used to examine redox shifts after ceramide exposure. While undifferentiated P19 cells were resistant to ceramide exposure, neuronally differentiated P19 cells exhibited an oxidizing shift. Consistent with these observations, GSH E h curves revealed a shift to a more oxidized state in C2 treated embryos without increasing apoptosis or changing Pax3 expression, however cell proliferation was lower. Neural tube defects were observed in 45% of chick embryos exposed to C2, compared to 12% in control embryos. Conclusions C2 exposure during critical developmental stages increased the frequency of NTDs in the avian model. Increased ROS generation in cell culture, along with the more oxidative GSH E h profiles of C2 exposed cells and embryos, support a model wherein ceramide affects neural tube closure via altered tissue redox environments.

show abstract

Section: Discussionmentioning

confidence: 99%

Ceramide: a novel inducer for neural tube defects

Ross

Piorczynski

Harvey

et al. 2019

Developmental Dynamics

View full text Add to dashboard Cite

show abstract

“…Mitochondrial outer membrane permeabilization (MOMP) is a critical step in apoptosis. Ceramide is considered to be the main substance that induces MOMP, which is a key event in apoptotic signaling through the formation of ceramide channels to facilitate the passage of proteins released during MOMP . Ganesan et al .…”

Section: Discussionmentioning

confidence: 99%

The sphingosine kinase 2 inhibitor ABC294640 displays anti‐non‐small cell lung cancer activities in vitro and in vivo

Dai

Smith

Foroozesh

et al. 2018

Intl Journal of Cancer

View full text Add to dashboard Cite

Non-small cell lung cancer (NSCLC) accounts for about 85-90% of lung cancer cases, and is the number one killer among cancers in the United States. The majorities of lung cancer patients do not respond well to conventional chemo- and/or radio-therapeutic regimens, and have a dismal 5-year survival rate of ∼15%. The recent introduction of targeted therapy and immunotherapy gives new hopes to NSCLC patients, but even with these agents, not all patients respond, and responses are rarely complete. Thus, there is still an urgent need to identify new therapeutic targets in NSCLC and develop novel anti-cancer agents. Sphingosine kinase 2 (SphK2) is one of the key enzymes in sphingolipid metabolism. SphK2 expression predicts poor survival in NSCLC patients, and is associated with Gefitinib-resistance. In this study, the anti-NSCLC activities of ABC294640, the only first-in-class orally available inhibitor of SphK2, were explored. The results obtained indicate that ABC294640 treatment causes significant NSCLC cell apoptosis, cell cycle arrest and suppression of tumor growth in vitro and in vivo. Moreover, lipidomics analyses revealed the complete signature of ceramide and dihydro(dh)-ceramide species in the NSCLC cell-lines with or without ABC294640 treatment. These findings indicate that sphingolipid metabolism targeted therapy may be developed as a promising strategy against NSCLC.

show abstract

“…Formation of ceramide channels does not require any auxiliary proteins but is disrupted by anti-apoptotic Bcl2 proteins (Chang et al, 2015;Siskind et al, 2008). Thus, the pore-forming activity of ceramides has been put forward as a potential mechanism for releasing pro-apoptotic proteins during the induction phase of apoptosis (Colombini, 2016).…”

Section: Discussionmentioning

confidence: 99%

Diverting CERT-mediated ceramide transport to mitochondria triggers Bax-dependent apoptosis

Jain

Beutel

Ebell

et al. 2017

Journal of Cell Science

View full text Add to dashboard Cite

A deregulation of ceramide biosynthesis in the endoplasmic reticulum (ER) is frequently linked to induction of mitochondrial apoptosis. Although in vitro studies suggest that ceramides might initiate cell death by acting directly on mitochondria, their actual contribution to the apoptotic response in living cells is unclear. Here, we have analyzed the consequences of targeting the biosynthetic flow of ceramides to mitochondria using a ceramide transfer protein (encoded by COL4A3BP) equipped with an OMM anchor, mitoCERT. Cells expressing mitoCERT import ceramides into mitochondria and undergo Bax-dependent apoptosis. Apoptosis induction by mitoCERT was abolished through (i) removal of its ceramide transfer domain, (ii) disruption of its interaction with VAMPassociated proteins (VAPs) in the ER, (iii) addition of antagonistic CERT inhibitor HPA12, (iv) blocking de novo ceramide synthesis and (v) targeting of a bacterial ceramidase to mitochondria. Our data provide the first demonstration that translocation of ER ceramides to mitochondria specifically commits cells to death and establish mitoCERT as a valuable new tool to unravel the molecular principles underlying ceramide-mediated apoptosis.

show abstract

Ceramide channels: destabilization by Bcl-xL and role in apoptosis

Cited by 50 publications

References 55 publications

Ceramide: a novel inducer for neural tube defects

Ceramide: a novel inducer for neural tube defects

The sphingosine kinase 2 inhibitor ABC294640 displays anti‐non‐small cell lung cancer activities in vitro and in vivo

Diverting CERT-mediated ceramide transport to mitochondria triggers Bax-dependent apoptosis

Contact Info

Product

Resources

About