Eleostearic acid induces RIP1-mediated atypical apoptosis in a kinase-independent manner via ERK phosphorylation, ROS generation and mitochondrial dysfunction

Obitsu, Saemi; Sakata, Kozue; Teshima, Reiko; Kondo, Kazunari

doi:10.1038/cddis.2013.188

Cited by 22 publications

(16 citation statements)

References 40 publications

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“…Prior to its identification as a necroptosis-inducer, ESA was shown to reduce growth of a human colon cancer in mice [28,29]. Another report showed that ESA induces RIPK1-mediated necroptosis of tumor cells via generation of ROS and ATP reduction without detectable effects on normal cells [27]. Our finding that ESA induced necroptosis in OVSAHO cells (Fig.…”

Section: α-Eleostearic Acid Reduces Survival Of Transformed Fte and Hsupporting

confidence: 54%

“…We chose to test induction of necroptosis in OVSAHO cells using P4, TNFα, or (9Z,11E,13E)-octadecatrienoic acid, also known as α-eleostearic acid or ESA. ESA has been demonstrated to induce necroptosis in tumor cells [27] and reduce human colon cancer growth in mice [28,29]. OVSAHO cells are PGR positive, TP53-mutant, have a homozygous BRCA2 deletion, and are considered highly-representative of HGSOC tumors [30].…”

Section: Established Hgsoc Cells Maintain the Capacity To Activate Nementioning

confidence: 99%

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Eliciting OTUD3/RIPK-Dependent Necroptosis to Prevent Epithelial Ovarian Cancer

Johnson

Bales

Bitler

et al. 2020

Preprint

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Background: There is an urgent need for early prevention strategies against high grade serous ovarian carcinoma (HGSOC), the deadliest gynecologic malignancy. Transformed p53-null fallopian tube epithelium (FTE) cells are precursors of HGSOC that may be eliminated by inducing necroptosis, a programmed form of inflammatory cell death. Induction of necroptosis is dependent upon activation of receptor-interacting serine/threonine-protein kinases 1 and 3 (RIPK1/3). TNFα and progesterone (P4) effectively promote necroptosis. In this study, we explore the activation of necroptosis as an approach to inhibit HGSOC progression.Methods: Using gene ontology sets as a reference, we analyzed publicly available datasets of HGSOC to correlate the expression of necroptosis effectors to clinical outcomes. Using in vitro models of HGSOC we evaluated the effect of TNFα, P4, and α-eleostearic acid on necroptosis.In parallel, the necroptosis inhibitor Necrostatin-1 was used to confirm necroptosis-specific cell death.Results: Expression of the P4 receptor (PGR) was sharply reduced in a HGSOC cohort compared to normal, nonmalignant FTE. However, several genes involved in necroptosis signaling were elevated in HGSOC, including TNF and RIPK1. Increased expression of PGR, the necroptosis effectors TNF and RIPK1/3, as well as ovarian tumor domain-containing deubiquitinase 3 (OTUD3) were associated with higher overall survival in 484 HGSOC cases.HGSOC cells activated necroptosis in response to P4, TNFα, and α-eleostearic acid treatment, while P4 or TNFα treatment of HGSOC cells increased TNF, RIPK1, and OTUD3 expression.OTUD3 is a putative tumor suppressor that stabilizes PTEN and is hypothesized to be functionally similar to the necroptosis inducer, OTUD7B. shRNA knockdown of OTUD3 resulted in decreased PTEN protein and RIPK1 protein. Conclusions:We conclude that necroptosis activation may be a viable prevention strategy that leads to the elimination of transformed FTE "founder" cells and prevents HGSOC tumorigenesis.Our data indicate that HGSOC cells activate necroptosis in response to P4, TNFα, and αeleostearic acid, suggesting that established HGSOC cells may also be eliminated by activating necroptosis. # Log2 fold change of HGSOC (n=11) compared to FTE (n=24) * P-value corrected for false-discovery rate by Benjamini-Hochberg method

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Section: α-Eleostearic Acid Reduces Survival Of Transformed Fte and Hsupporting

confidence: 54%

Section: Established Hgsoc Cells Maintain the Capacity To Activate Nementioning

confidence: 99%

Eliciting OTUD3/RIPK-Dependent Necroptosis to Prevent Epithelial Ovarian Cancer

Johnson

Bales

Bitler

et al. 2020

Preprint

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“…The following validated siRNAs were used for rat AIF and Atg5 knockdown, respectively [10, 11]. siAIF: 5’-cauagaagcaugcagcaucuccugc-3’; siAtg5: 5’-gguuuggacgaauuccaacuuguuu-3’.…”

Section: Methodsmentioning

confidence: 99%

Caspase-Independent Pathway is Related to Nilotinib Cytotoxicity in Cultured Cardiomyocytes

Yang

Zhang

Wang

et al. 2017

Cell Physiol Biochem

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Background/Aims: Cardiotoxicity is a predominant side-effect of nilotinib during chronic myeloid leukemia treatment. The underlying molecular mechanism remains unclear. The role of autophagy and mitochondrial signaling was investigated in nilotinib-treated cardiac H9C2 cells. Methods: Cytotoxicity was assessed using Cell Death Detection kit. Immunoblot and immunofluorescence staining was performed, and cathepsin B and caspase3 activity was assessed in nilotinib-treated H9C2 cells with or without distinct pathway inhibitor or specific siRNA. Results: Nilotinib time- and dose-dependently induced H9C2 apoptosis, which was not completely prevented by the pan caspase inhibitor z-VAD-fmk. Following nilotinib treatment, mitochondrial membrane potential decreased significantly accompanied with remarkable morphological changes. Nuclear translocation of mitochondrial apoptosis inducing factor (AIF) and increased p53 was detected in nilotinib-treated cells. AIF knockdown prevented nilotinib-induced increase of p53 and apoptosis. Additionally, increased cathepsin B activity was detected, and inhibition of cathepsin B by CA-074Me prevented nilotinib-induced apoptosis and nuclear translocation of AIF. Moreover, increased Atg5 and transition of LC3-I to LC3-II was revealed following nilotinib treatment. Increased cathepsin B activity and apoptosis by nilotinib was significantly prohibited by specific autophagy inhibitor bafilomycin A and Atg5 knockdown. Conclusion: Our findings demonstrate that nilotinib increases autophagy and cathepsin B activity, leading to mitochondrial AIF release and nuclear translocation, which is responsible for p53 and apoptosis induction in H9C2 cells.

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“…2) [85]. Finally, RIP1 was recently reported to be involved in eleostearic acid-induced atypical apoptosis by promoting reactive oxygen species (ROS) production [86]. …”

Section: Non-necrotic Function Of Rip1 In Apoptosis and Inflammatomentioning

confidence: 99%

Necrosis-dependent and independent signaling of the RIP kinases in inflammation

Moriwaki

Chan

2014

Cytokine & Growth Factor Reviews

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It is now widely accepted that some forms of necrosis are controlled by a dedicated signaling pathway triggered by various cell surface and intracellular receptors. This regulated form of necrosis is mediated by the kinase activity of receptor-interacting protein kinase 1 (RIP1/RIPK1) and/or RIP3/RIPK3. A number of studies using the RIP1 kinase inhibitor Necrostatin-1 (Nec-1) and its derivatives, or RIP3-deficient mice demonstrated that RIP1 and RIP3 are involved in various infectious and sterile inflammatory diseases. As a consequence, these specific phenotypes were construed to depend on necrosis. However, emerging evidence indicates that the RIP1 kinase activity and RIP3 can also control apoptosis and inflammatory cytokine production independent of necrosis. Therefore, we may need to re-interpret conclusions drawn based on loss of RIP1 or RIP3 functions in in vivo models. We propose that studies of RIP1 and RIP3 in different inflammatory responses need to consider cell death-dependent and independent mechanisms of the RIP kinases.

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Eleostearic acid induces RIP1-mediated atypical apoptosis in a kinase-independent manner via ERK phosphorylation, ROS generation and mitochondrial dysfunction

Cited by 22 publications

References 40 publications

Eliciting OTUD3/RIPK-Dependent Necroptosis to Prevent Epithelial Ovarian Cancer

Eliciting OTUD3/RIPK-Dependent Necroptosis to Prevent Epithelial Ovarian Cancer

Caspase-Independent Pathway is Related to Nilotinib Cytotoxicity in Cultured Cardiomyocytes

Necrosis-dependent and independent signaling of the RIP kinases in inflammation

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