scholarly journals Dexamethasone Induces Apoptosis in Proliferative Chondrocytes through Activation of Caspases and Suppression of the Akt-Phosphatidylinositol 3′-Kinase Signaling Pathway

Endocrinology ◽  
2005 ◽  
Vol 146 (3) ◽  
pp. 1391-1397 ◽  
Author(s):  
Dionisios Chrysis ◽  
Farasat Zaman ◽  
Andrei S. Chagin ◽  
Masaharu Takigawa ◽  
Lars Sävendahl
Keyword(s):  
Signaling Pathway ◽  
Pi3k Pathway ◽  
Caspase 8 ◽  
Phosphatidylinositol 3 Kinase ◽  
Akt Inhibitor ◽  
Growth Plate Chondrocytes ◽  
Igf I ◽  
Induced Apoptosis ◽  
Phosphatidylinositol 3

Although glucocorticoids are known to induce apoptosis in chondrocytes, the mechanisms for this effect and the potential antiapoptotic role of IGF-I are unknown. To address this, we studied the effects of dexamethasone (Dexa) on apoptosis in the HCS-2/8 chondrocytic cell line. Dexa (25 μm) increased apoptosis (cell death ELISA) by 39% and 45% after 48 and 72 h, respectively (P < 0.01 and P < 0.05, respectively). IGF-I (100 ng/ml) decreased Dexa-induced apoptosis to levels similar to control cells. Apoptosis was associated with cleavage of poly-ADP-ribose polymerase (PARP) and α-fodrin and activation of caspases-8, -9, and -3 (Western), an effect that was counteracted when chondrocytes were cocultured with Dexa + IGF-I. Inhibitors for caspases-8, -9, and -3 (50 μm each) equally suppressed Dexa-induced apoptosis (P < 0.01). Time-response experiments showed that caspase-8 was activated earlier (at 12 h) than caspase-9 (at 36 h). We studied the phosphatidylinositol 3′-kinase (PI3K) pathway to further investigate the mechanisms of Dexa-induced apoptosis. Dexa decreased Akt phosphorylation by 93% (P < 0.001) without affecting total Akt and increased the p85α subunit 4-fold. The Akt inhibitor SH-6 (10 μm) increased apoptosis by 54% (P < 0.001). When combining Dexa with SH-6, apoptosis was not further increased, showing that Dexa-induced apoptosis is mediated through inhibition of the PI3K pathway. Addition of IGF-I to SH-6- or Dexa + SH-6-treated cells decreased apoptosis by 21.2% (P < 0.001) and 20.6% (P < 0.001), respectively. We conclude that Dexa-induced apoptosis is caspase dependent with an early activation of caspase-8. IGF-I can rescue chondrocytes from Dexa-induced apoptosis partially through the activation of other pathways than the PI3K signaling pathway. Based on our in vitro data, we speculate that in vivo treatment with glucocorticoids may diminish longitudinal growth by increasing apoptosis of proliferative growth plate chondrocytes.

Targeting Bcl-2 family proteins modulates the sensitivity of B-cell lymphoma to rituximab-induced apoptosis

Blood ◽  
2008 ◽  
Vol 112 (8) ◽  
pp. 3312-3321 ◽  
Author(s):  
Claudia Stolz ◽  
Georg Hess ◽  
Patricia S. Hähnel ◽  
Florian Grabellus ◽  
Sandra Hoffarth ◽  
...  
Keyword(s):  
B Cell ◽  
Kinase Inhibitors ◽  
B Cell Lymphoma ◽  
Resistance Pattern ◽  
Phosphatidylinositol 3 Kinase ◽  
Endogenous Expression ◽  
Induced Apoptosis ◽  
Phosphatidylinositol 3

Abstract The chimeric monoclonal antibody rituximab is the standard of care for patients with B-cell non-Hodgkin lymphoma (B-NHL). Rituximab mediates complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity of CD20-positive human B cells. In addition, rituximab sensitizes B-NHL cells to cytotoxic chemotherapy and has direct apoptotic and antiproliferative effects. Whereas expression of the CD20 antigen is a natural prerequisite for rituximab sensitivity, cell-autonomous factors determining the response of B-NHL to rituximab are less defined. To this end, we have studied rituximab-induced apoptosis in human B-NHL models. We find that rituximab directly triggers apoptosis via the mitochondrial pathway of caspase activation. Expression of antiapoptotic Bcl-xL confers resistance against rituximab-induced apoptosis in vitro and rituximab treatment of xenografted B-NHL in vivo. B-NHL cells insensitive to rituximab-induced apoptosis exhibit increased endogenous expression of multiple antiapoptotic Bcl-2 family proteins, or activation of phosphatidylinositol-3-kinase signaling resulting in up-regulation of Mcl-1. The former resistance pattern is overcome by treatment with the BH3-mimetic ABT-737, the latter by combining rituximab with pharmacologic phosphatidylinositol-3-kinase inhibitors. In conclusion, sensitivity of B-NHL cells to rituximab-induced apoptosis is determined at the level of mitochondria. Pharmacologic modulation of Bcl-2 family proteins or their upstream regulators is a promising strategy to overcome rituximab resistance.

scholarly journals Solenopsin, the alkaloidal component of the fire ant (Solenopsis invicta), is a naturally occurring inhibitor of phosphatidylinositol-3-kinase signaling and angiogenesis

Blood ◽  
2006 ◽  
Vol 109 (2) ◽  
pp. 560-565 ◽  
Author(s):  
Jack L. Arbiser ◽  
Tweeny Kau ◽  
Martha Konar ◽  
Krishna Narra ◽  
Ramani Ramchandran ◽  
...  
Keyword(s):  
Angiogenesis Inhibitor ◽  
Angiogenesis Inhibitors ◽  
Angiogenic Factor ◽  
Phosphatidylinositol 3 Kinase ◽  
Angiogenesis Assay ◽  
Downstream Effector ◽  
Induced Apoptosis ◽  
Cancer Multiple ◽  
Phosphatidylinositol 3

Abstract Phosphatidylinositol-3-kinase (PI3K), and its downstream effector Akt, or protein kinase Bα (PKBα), play a major regulatory role in control of apoptosis, proliferation, and angiogenesis. PI3K and Akt are amplified or overexpressed in a number of malignancies, including sarcomas, ovarian cancer, multiple myeloma, and melanoma. This pathway regulates production of the potent angiogenic factor vascular endothelial growth factor (VEGF), and protects tumor cells against both chemotherapy and reactive oxygen–induced apoptosis through phosphorylation of substrates such as apoptotic peptidase–activating factor-1 (APAF-1), forkhead proteins, and caspase 9. Given its diverse actions, compounds that suppress the PI3K/Akt pathway have potential pharmacologic utility as angiogenesis inhibitors and antineoplastic agents. Using the SVR angiogenesis assay, a screen of natural products, we isolated the alkaloid solenopsin, and found that it is a potent angiogenesis inhibitor. We also found that solenopsin inhibits the PI3K signaling pathway in cells upstream of PI3K, which may underlie its affects on angiogenesis. Consistent with inhibition of the activation of PI3K, solenopsin prevented the phosphorylation of Akt and the phosphorylation of its substrate forkhead box 01a (FOXO1a), a member of the forkhead family of transcription factors. Interestingly, solenopsin also inhibited Akt-1 activity in an ATP-competitive manner in vitro without affecting 27 of 28 other protein kinases tested.

scholarly journals Insulin-like growth factor induces phosphorylation of immunoreactive insulin receptor substrate and its association with phosphatidylinositol-3 kinase in human thymocytes.

1995 ◽  
Vol 182 (2) ◽  
pp. 593-597 ◽  
Author(s):  
R Kooijman ◽  
J J Lauf ◽  
A C Kappers ◽  
G T Rijkers
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Insulin Receptor ◽  
Signaling Pathway ◽  
Insulin Receptor Substrate ◽  
Type I ◽  
Insulin Like Growth Factor ◽  
Phosphatidylinositol 3 Kinase ◽  
Igf I ◽  
Phosphatidylinositol 3

Insulin receptor substrate 1 (IRS-1) is the principle cellular substrate for insulin and insulin-like growth factor I (IGF-I) receptor signaling. After phosphorylation of tyrosine residues within the YMXM or YXXM motifs, IRS-1 associates with phosphatidylinositol-3 kinase (PI3K). This signaling pathway and the presence of an IRS-1-like molecule have been demonstrated in IRS-1-transfected and in nontransfected hematopoietic cell lines, respectively. IGF-I has been implicated in lymphocyte development and function, and recently, we showed that functional type-I IGF receptors are present on human thymocytes and peripheral T cells. In this study, we addressed IGF-I signal transduction in nontransformed, freshly isolated, human thymocytes, as well as in blood T cells. Using Western blot analysis, we found that IGF-I induced phosphorylation of a 160-180-kD protein (pp170) in human thymocytes and that phosphorylated pp170 becomes associated with PI3K and is recognized by anti-IRS-1. In blood T cells, this immunoreactive IRS-1 (irIRS-1) is less abundantly expressed than in thymocytes, as assessed with immunoblotting. As a consequence, phosphorylated pp170 was not or hardly detectable after stimulation with IGF-I, and irIRS-1 was not detected in PI3K immunoprecipitates from lysates of IGF-I-stimulated T cells. However, IGF-I induced the tyrosine phosphorylation of other cellular proteins, indicating that differential expression of irIRS-1 contributes to a distinct signaling pathway in T cells.

Patient-Derived Stem Cell Surrogates of Acute Lymphoblastic Leukemia Are Sensitive towards TRAIL-Induced Apoptosis Which Is Determined at the Level of Receptor-Proximal Signaling

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2133-2133
Author(s):  
Katja Schneider ◽  
Catarina Castro Alves ◽  
Irmela Jeremias
Keyword(s):  
Stem Cell ◽  
Signaling Pathway ◽  
Tumor Cells ◽  
Lymphoblastic Leukemia ◽  
Caspase 8 ◽  
Leukemia Stem Cell ◽  
Induced Apoptosis ◽  
Proximal Signaling ◽  
Trail Signaling

Abstract Abstract 2133 Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family and a promising future cytotoxic drug for cancer treatment. TRAIL induces apoptosis in tumor cells with no apparent toxicity in patients. Here, we studied the effect and signaling mechanisms of TRAIL on patient-derived acute lymphoblastic leukemia (ALL) cells and stem cell surrogates. In 171 fresh primary acute leukemia tumor cells, TRAIL induced apoptosis in 28 % of samples and survival in 13 % of samples, while TRAIL had no effect on the remaining majority of samples (59 %). After amplification of 20 samples in NOD/SCID mice, xenograft ALL-cells were isolated from spleens of diseased mice and used for in vitro assays. In the 20 xenograft ALL-samples, TRAIL induced apoptosis in 5 samples (20 %), had no effect on 12 samples (60 %) and induced survival on 3 samples (15 %) and thus in similar frequencies as in primary tumor cells. TRAIL-induced apoptosis in vitro remained unaltered upon passaging of cells through several generations of mice. To study the effect of TRAIL on leukemia stem cell surrogates, frequency of leukemia-initiating cells (LICs) was determined by limiting dilution analysis. Fresh xenograft ALL-cells were treated with and without TRAIL in vitro and were transplanted into 25 mice per treatment group in different absolute cell numbers. After 3 months, engraftment was determined in all mice by FACscan and immunohistochemistry of bone marrow, spleen and liver, and LIC frequency was calculated. TRAIL induced 60 % apoptosis in leukemia bulk cells and 75 % apoptosis in LICs suggesting that TRAIL induced significant apoptosis in LICs of this xenograft sample. We next asked which signaling mechanisms determine apoptosis sensitivity of patient-derived ALL cells towards TRAIL. The first signaling steps upon stimulation with TRAIL consist in binding of TRAIL to its receptors and recruitment of the adapter molecule and the proximal initiator caspase Caspase-8 to form the so called “death inducing signaling complex” (DISC). The expression pattern of intracellular DISC proteins was similar between TRAIL-sensitive and TRAIL-resistant samples. In contrast to other tumor entities, expression of pro-apoptotic TRAIL-receptors correlated well to TRAIL-induced apoptosis in patient-derived ALL cells. TRAIL-sensitive, but not TRAIL-resistant samples showed significant binding of TRAIL to the surface of living cells and cytosolic activation of Caspase-3. Accordingly, DISC immune precipitations showed that TRAIL bound TRAIL-receptor 1 and 2 which recruited FADD leading to cleavage of Caspase-8 and FLIP at the DISC in sensitive, but not resistant samples. Taken together our data indicate that in patient-derived ALL cells, TRAIL-sensitivity is regulated at the receptor-proximal signaling pathway, where sufficient binding between TRAIL and its receptors is required to enable recruitment of FADD, activation of Caspase-8 and induction of apoptosis. Our data suggest that sensitivity for TRAIL-induced apoptosis is regulated at the receptor-proximal TRAIL signaling pathway in patient-derived ALL cells. Characterization of the receptor-proximal TRAIL signaling pathway might thus allow the prediction of TRAIL function for potential individualized treatment strategies. As TRAIL is able to induce apoptosis in LICs as leukemia stem cell surrogates, TRAIL might represent an interesting future drug for the treatment of ALL. Disclosures: No relevant conflicts of interest to declare.

Taurine attenuates acrylamide-induced apoptosis via a PI3K/AKT-dependent manner

2018 ◽  
Vol 37 (12) ◽  
pp. 1249-1257 ◽  
Author(s):  
G Sun ◽  
X Wang ◽  
T Li ◽  
S Qu ◽  
J Sun
Keyword(s):  
Signaling Pathway ◽  
Akt Signaling ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Dependent Manner ◽  
Akt Signaling Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Akt Inhibitor ◽  
Higher Temperature ◽  
Induced Apoptosis

As a potent neurotoxic agent, acrylamide (ACR) is formed in food processing at higher temperature. Taurine (TAU), a nonessential amino acid, is used to cure neurodegenerative disorders, followed by activation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway. In this article, we certified that antiapoptotic efficacy of TAU in vivo and vitro. ACR-treated rats received TAU by drinking water 2 weeks after ACR intoxication. The results showed that in treated rats, TAU alleviated ACR-induced neuronal apoptosis, which was associated with the activation of PI3K/AKT signaling pathway. TAU attenuated apoptosis caused by ACR through observing terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells, measure of protein expression of Bcl-2, Bax, and caspase 3 activity. TAU-induced antiapoptotic effect is PI3K/AKT-dependent, which was proved in ACR-intoxicated ventral spinal cord 4.1 cells in the presence of AKT inhibitor, MK-2206. Therefore, our results demonstrated that TAU-attenuated ACR-induced apoptosis in vivo through a PI3K/AKT-dependent manner provided new sights in the molecular mechanism of TAU protection against ACR-induced neurotoxicity.

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