Protein Kinase C and Apoptosis

Reyland, Mary E.

doi:10.1007/978-1-59745-199-4_2

Cited by 36 publications

(48 citation statements)

References 211 publications

(248 reference statements)

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“…It should be noted that PKC-delta-p38 MAPK activation induces apoptosis, and the nuclear localization of PKC-delta is required for this action. 32 Notably, in retinas from diabetic mice treated with CaD, apart from the lower levels of PKCdelta in comparison with diabetic mice treated with vehicle, their localization was mainly cytoplasmatic rather than nuclear.…”

Section: Mechanisms Of Action Of Cadmentioning

confidence: 93%

Calcium Dobesilate Prevents Neurodegeneration and Vascular Leakage in Experimental Diabetes

Solà-Adell

Bogdanov

Hernández

et al. 2017

Current Eye Research

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Purpose: The mechanisms involved in the reported beneficial effects of Calcium dobesilate monohydrate (CaD) for the treatment of diabetic retinopathy (DR) remain to be elucidated. The main aim of the present study is to examine whether CaD prevents early events in the pathogenesis of DR such as neurodegeneration and vascular leakage. In addition, putative mediators of both neurodegeneration (glutamate/GLAST, ET-1/ETB receptor) and early microvascular impairment (ET-1/ETA receptor, oxidative stress, VEGF, and the PKC-delta-p38 MAPK pathway) have been examined. Methods: Diabetic (db/db) mice were randomly assigned to daily oral treatment with CaD (200 mg/Kg/ day) (n = 12) or vehicle (n = 12) for 14 days. In addition, 12 non-diabetic (db/+) mice matched by age were used as the control group. Functional abnormalities were assessed by electroretinography. Neurodegeneration and microvascular abnormalities were evaluated by immunohistochemistry and Western blot. Glutamate was determined by HPLC. Results: CaD significantly decreased glial activation and apoptosis and produced a significant improvement in the electroretinogram parameters. Mechanistically, CaD prevented the diabetes-induced upregulation of ET-1 and its cognate receptors (ETA-R and ETB-R), which are involved in microvascular impairment and neurodegeneration, respectively. In addition, treatment with CaD downregulated GLAST, the main glutamate transporter, and accordingly prevented the increase in glutamate. Finally, CaD prevented oxidative stress, and the upregulation of VEGF and PKC delta-p38 MAPK pathway induced by diabetes, thus resulting in a significant reduction in vascular leakage.Conclusions: Our findings demonstrate for the first time that CaD exerts neuroprotection in an experimental model of DR. In addition, we provide first evidence that CaD prevents the overexpression of ET-1 and its receptors in the diabetic retina. These beneficial effects on the neurovascular unit could pave the way for clinical trials addressed to confirm the effectiveness of CaD in very early stages of DR. ARTICLE HISTORY

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Section: Mechanisms Of Action Of Cadmentioning

confidence: 93%

Calcium Dobesilate Prevents Neurodegeneration and Vascular Leakage in Experimental Diabetes

Solà-Adell

Bogdanov

Hernández

et al. 2017

Current Eye Research

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“…The protein kinase C (PKC) family of Ser/Thr kinases regulates several cellular functions such as cell cycle, cell survival, malignant transformation, and apoptosis (6). It is generally believed that the activation of PKC isoforms contributes to cancer, but downregulation rather than activation of PKCd has been associated with tumor progression (7).…”

Section: Introductionmentioning

confidence: 99%

“…While some studies point to a role of PKCd in cell survival and the antiapoptotic response, most studies indicate that the PKCd isoform promotes suppression of cell proliferation and apoptosis induction. PKCd is activated by genotoxins, oxidative stress, and death receptors, and its inhibition blocks apoptosis induced by a variety of stimuli in many cell types (6). In the case of prostate cancer, most reports indicate that PKCd expression is required to induce apoptosis by anticancer drugs or death receptors (8)(9)(10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Loss of PKCδ Induces Prostate Cancer Resistance to Paclitaxel through Activation of Wnt/β-Catenin Pathway and Mcl-1 Accumulation

Flores

Castilla

Gasca

et al. 2016

Molecular Cancer Therapeutics

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Prostate cancer is the leading cause of cancer-related death among men in developed countries. Although castration therapy is initially effective, prostate cancers progress to hormone-refractory disease and in this case taxane-based chemotherapy is widely used. Castration-resistant prostate cancer cells often develop resistance to chemotherapy agents and the search for new therapeutic strategies is necessary. In this article, we demonstrate that PKCd silencing favors mitotic arrest after paclitaxel treatment in PC3 and LNCaP cells; however, this is associated with resistance to paclitaxel-induced apoptosis. In prostate cancer cells, PKCd seems to exert a proapoptotic role, acting as a negative regulator of the canonical Wnt/b-catenin pathway. PKCd silencing induces activation of Wnt/b-catenin pathway and the expression of its target genes, including Aurora kinase A, which is involved in activation of Akt and both factors play a key role in GSK3b inactivation and consequently in the stabilization of b-catenin and antiapoptotic protein Mcl-1. We also show that combined treatments with paclitaxel and Wnt/b-catenin or Akt inhibitors improve the apoptotic response to paclitaxel, even in the absence of PKCd. Finally, we observe that high Gleason score prostate tumors lose PKCd expression and this correlates with higher activation of b-catenin, inactivation of GSK3b, and higher levels of Aurora kinase A and Mcl-1 proteins. These findings suggest that targeting Wnt/b-catenin or Akt pathways may increase the efficacy of taxane chemotherapy in advanced human prostate cancers that have lost PKCd expression.

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“…Mechanistically, PKC-␦ can promote apoptosis at multiple levels, including the activation of apoptotic gene expression, phosphorylation of caspases, interaction with apoptotic regulators, remodeling of cell membranes, and regulation of mitochondria. 28,29 A recent study further suggested a role for PKC-␦ in ER-mitochondria crosstalk during ER-stress-induced apoptosis. 30 It remains unknown how PKC-␦ regulates Bax during apoptosis.…”

Section: Discussionmentioning

confidence: 98%

“…On the other hand, PKC-␦ has been suggested to be directly involved in the regulation of apoptosis. 28,29 A proapoptotic role for PKC-␦ has been demonstrated in a variety of experimental models. Mechanistically, PKC-␦ can promote apoptosis at multiple levels, including the activation of apoptotic gene expression, phosphorylation of caspases, interaction with apoptotic regulators, remodeling of cell membranes, and regulation of mitochondria.…”

Section: Discussionmentioning

confidence: 99%

PKC-δ Promotes Renal Tubular Cell Apoptosis Associated with Proteinuria

Li¹,

Pabla²,

Wei³

et al. 2010

Journal of the American Society of Nephrology

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Proteinuria may contribute to progressive renal damage by inducing tubulointerstitial inflammation, fibrosis, and tubular cell injury and death, but the mechanisms underlying these pathologic changes remain largely unknown. Here, in a rat kidney proximal tubular cell line (RPTC), albumin induced apoptosis in a time-and dose-dependent manner. Caspase activation accompanied albumin-induced apoptosis, and general caspase inhibitors could suppress this activation. In addition, Bcl-2 transfection inhibited apoptosis and attenuated albumin-induced Bax translocation to mitochondria and cytochrome c release from the organelles, further confirming a role for the intrinsic pathway of apoptosis in albuminuria-associated tubular apoptosis. We observed phosphorylation and activation of PKC-␦ early during treatment of RPTC cells with albumin. Rottlerin, a pharmacologic inhibitor of PKC-␦, suppressed albumin-induced Bax translocation, cytochrome c release, and apoptosis. Moreover, a dominant-negative mutant of PKC-␦ blocked albumin-induced apoptosis in RPTC cells. In vivo, we observed activated PKC-␦ in proteinuric kidneys of streptozotocin-induced diabetic mice and in kidneys after direct albumin overload. Notably, albumin overload induced apoptosis in renal tubules, which was less severe in PKC-␦-knockout mice. Taken together, these results suggest that activation of PKC-␦ promotes tubular cell injury and death during albuminuria, broadening our understanding of the pathogenesis of progressive proteinuric kidney diseases.

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Protein Kinase C and Apoptosis

Cited by 36 publications

References 211 publications

Calcium Dobesilate Prevents Neurodegeneration and Vascular Leakage in Experimental Diabetes

Calcium Dobesilate Prevents Neurodegeneration and Vascular Leakage in Experimental Diabetes

Loss of PKCδ Induces Prostate Cancer Resistance to Paclitaxel through Activation of Wnt/β-Catenin Pathway and Mcl-1 Accumulation

PKC-δ Promotes Renal Tubular Cell Apoptosis Associated with Proteinuria

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