Protein Kinase C δ Activation and Translocation to the Nucleus Are Required for Fatty Acid-Induced Apoptosis of Insulin-Secreting Cells

Eitel, Katrin; Staiger, Harald; Rieger, Johannes; Mischak, Harald; Brandhorst, Heide; Brendel, Mathias D.; Bretzel, Reinhard G.; Häring, Hans‐Ulrich; Kellerer, Monika

doi:10.2337/diabetes.52.4.991

Cited by 131 publications

(113 citation statements)

References 46 publications

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“…The accumulation of DAG observed in palmitate-treated cells may participate in the induction of apoptosis by acting on DAG-responsive enzymes like protein kinases C (PKC) (51), as shown recently in ␤-cells for palmitate-induced PKC␦ activation (52). In contrast, the channeling of palmitate into TG stores induced by oleate cosupplementation may contribute to rescue cells from palmitate-induced apoptosis by redirecting palmitate away from pathways leading to apoptosis.…”

Section: Discussionmentioning

confidence: 96%

Saturated Fatty Acid-induced Apoptosis in MDA-MB-231 Breast Cancer Cells

Hardy

El-Assaad

Przybytkowski

et al. 2003

Journal of Biological Chemistry

248

243

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Little is known about the biochemical basis of the action of free fatty acids (FFA) on breast cancer cell proliferation and apoptosis. Here we report that unsaturated FFAs stimulated the proliferation of human MDA-MB-231 breast cancer cells, whereas saturated FFAs inhibited it and caused apoptosis. Saturated FFA palmitate decreased the mitochondrial membrane potential and caused cytochrome c release. Palmitate-induced apoptosis was enhanced by the fat oxidation inhibitor etomoxir, whereas it was reduced by fatty-acyl CoA synthase inhibitor triacsin C. The non-metabolizable analog 2-bromopalmitate was not cytotoxic. This indicates that palmitate must be metabolized to exert its toxic effect but that its action does not involve fat oxidation. Pharmacological studies showed that the action of palmitate is not mediated via ceramides, reactive oxygen species, or changes in phosphatidylinositol 3-kinase activity. Palmitate caused early enhancement of cardiolipin turnover and decreased the levels of this mitochondrial phospholipid, which is necessary for cytochrome c retention. Cosupplementation of oleate, or increasing ␤-oxidation with the AMP-activated protein kinase activator, 5-aminoimidazole-4-carboxamide-1-␤-D-ribonucleoside, both restored cardiolipin levels and blocked palmitate-induced apoptosis. Oleate was preferentially metabolized to triglycerides, and oleate cosupplementation channeled palmitate esterification processes to triglycerides. Overexpression of Bcl-2 family members blocked palmitateinduced apoptosis. The results provide evidence that a decrease in cardiolipin levels and altered mitochondrial function are involved in palmitate-induced breast cancer cell death. They also suggest that the antiapoptotic action of oleate on palmitate-induced cell death involves both restoration of cardiolipin levels and redirection of palmitate esterification processes to triglycerides.

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Section: Discussionmentioning

confidence: 96%

Saturated Fatty Acid-induced Apoptosis in MDA-MB-231 Breast Cancer Cells

Hardy

El-Assaad

Przybytkowski

et al. 2003

Journal of Biological Chemistry

248

243

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“…PKCs can interact with the plasma membrane [11], golgi [12], and cytoskeleton [13]. More recently, it has become evident that some PKCs interact with mitochondria [14] and cell nuclei [15]. As a consequence, PKCs are involved in such diverse functions as differentiation, cell growth, apoptosis, gene expression, muscle contraction, metabolism, and endocytosis [16].…”

Section: A General Mechanism For Processing and Activation Of Pkcsmentioning

confidence: 99%

Protein kinase C as a stress sensor

Barnett

Madgwick

Takemoto

2007

Cellular Signalling

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While there are many reviews which examine the group of proteins known as protein kinase C (PKC), the focus of this article is to examine the cellular roles of two PKCs that are important for stress responses in neurological tissues (PKCγ and ε) and in cardiac tissues (PKCε). These two kinases, in particular, seem to have overlapping functions and interact with an identical target, connexin 43 (Cx43), a gap junction protein which is central to proper control of signals in both tissues. While PKCγ and PKCε both help protect neural tissue from ischemia, PKCε is the primary PKC isoform responsible for responding to decreased oxygen, or ischemia, in the heart. Both do this through Cx43.It is clear that both PKCγ and PKCε are necessary for protection from ischemia. However, the importance of these kinases has been inferred from preconditioning experiments which demonstrate that brief periods of hypoxia protect neurological and cardiac tissues from future insults, and that this depends on the activation, translocation, or ability for PKCγ and/or PKCε to interact with distinct cellular targets, especially Cx43.This review summarizes the recent findings which define the roles of PKCγ and PKCε in cardiac and neurological functions and their relationships to ischemia/reperfusion injury. In addition, a biochemical comparison of PKC γ and PKC ε and a proposed argument for why both forms are present in neurological tissue while only PKC ε is present in heart, are discussed. Finally, the biochemistry of PKCs and future directions for the field are discussed, in light of this new information.

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“…In some experiments, cells were incubated with NEFA. NEFA (SigmaAldrich, Taufkirchen, Germany) were bound to fatty-acidfree BSA as previously described [27].…”

Section: Cell Culturementioning

confidence: 99%

Insulin and its analogue glargine do not affect viability and proliferation of human coronary artery endothelial and smooth muscle cells

Staiger

Schweitzer³

et al. 2005

Diabetologia

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Aims/hypothesis: Present guidelines for the treatment of type 2 diabetes recommend HbA 1 c values of less than 7%. As beta cell function worsens during progress of the disease, insulin therapy is often necessary to achieve this ambitious goal. However, due to peripheral insulin resistance, many patients need rather high insulin dosages. In the light of the extremely high cardiovascular risk of diabetic patients, it is important to determine whether high concentrations of insulin or its frequently used analogues are harmful to the cardiovascular system. We therefore investigated the modulatory effects of regular human insulin and its analogue glargine on proliferation and apoptosis of human coronary artery endothelial cells (HCAECs) and human coronary artery smooth muscle cells (HCASMCs). Methods: Cells were treated with regular human insulin or insulin glargine. Proliferation was determined by [ 3 H]thymidine incorporation and by flow cytometric analysis of Ki-67 expression. Apoptosis was assessed by flow cytometry (cell cycle analysis and annexin V staining) and determination of caspase-3 activity. Results: HCAECs and HCASMCs treated with regular human insulin or insulin glargine did not show significant increases in DNA synthesis or Ki-67 expression. Administration of regular human insulin or insulin glargine did not modulate the extent of apoptotic events. No influence of insulin on lipoapoptotic vascular cell death could be detected.Conclusions/interpretation: Taken together, neither regular human insulin nor insulin glargine influences growth and apoptosis of human coronary artery cells in vitro. Our data do not suggest that regular human insulin or insulin glargine promote atherosclerosis through mechanisms affecting the cellularity of human coronary arteries.

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Protein Kinase C δ Activation and Translocation to the Nucleus Are Required for Fatty Acid-Induced Apoptosis of Insulin-Secreting Cells

Cited by 131 publications

References 46 publications

Saturated Fatty Acid-induced Apoptosis in MDA-MB-231 Breast Cancer Cells

Saturated Fatty Acid-induced Apoptosis in MDA-MB-231 Breast Cancer Cells

Protein kinase C as a stress sensor

Insulin and its analogue glargine do not affect viability and proliferation of human coronary artery endothelial and smooth muscle cells

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