Because we discovered Wee1 to alter Cdk2 phosphorylation as well as trigger apoptosis, we tested whether apoptosis could be induced by a more specific Cdk2inhibitor.
Our results indicate that an imbalance of Cdk-inhibitory activity triggers apoptosis, most likely through the disruption of the cyclin E/Cdk2 timer, since direct inhibition of cyclin E/Cdk2 also induces apoptosis.
These data indicate that specific inhibition of Cdk2 results in apoptosis in Xenopus embryos.
Since the overexpression of Wee1 not only alters cell cycle remodeling events (Figure ) and the concentration of DNA at the MBT (6 hr pf; Figure ), but also phosphorylates Cdk2 (Figure ), we wanted to determine whether inhibition of Cdk2 contributed to the induction of apoptosis.
Thus, down-regulation of hnRNP K activates caspase-3-mediated apoptosis similar to that observed in cells expressing expanded AUUCU repeats.
Targeted inactivation of hnRNP K triggers apoptosis whereas ectopic expression of hnRNP K rescues AUUCU–mediated apoptosis.
In contrast, ∼50% over-expression of hnRNP K () decreased the expanded AUUCU repeat-induced apoptosis by ∼30%, and this decrease in apoptosis is accompanied by reducedcaspase-3 activity (n = 3, p<0.05) ().
Apoptosis after COX-2inhibition with SC-58635 (50 micromol/L) was independent of BCL-2, BAX, and the phosphorylation status of AKT/PKB and BAD, but correlated with activation of caspase-9, caspase-3, and caspase-6.
In conclusion, selective inhibition of COX-2 leads to a marked growth inhibition of human liver tumor cells, based on the induction of apoptosis and inhibition of proliferation and, thus, may offer therapeutic and preventive potential in human hepatocarcinogenesis.
Santamaría B …
,
Benito-Martin A,
Ucero AC,
Aroeira LS,
Reyero A,
Vicent MJ,
Orzáez M,
Celdrán A,
Esteban J,
Selgas R,
Ruíz-Ortega M,
Cabrera ML,
Egido J,
Pérez-Payá E, Ortiz A » «
A nanoconjugate Apaf-1inhibitorprevents cytokine-induced apoptosis and promotes wound healing
By contrast, a polymeric nanoconjugate Apaf-1inhibitor protected from apoptosis and allowed wound healing and long-term recovery.
Chemical inhibition of Apaf-1 by a nanoconjugate molecule , , prevented mesothelial cell apoptosis induced by the combination of cytokines in cell culture and in vivo, suggesting that Apaf-1 is required for mesothelial cell death to occur.
A nanoconjugate Apaf-1inhibitor (PGA-peptoid QM56) inhibits caspase activation and apoptosis.
The proteasome is a hub for the regulation of many cellular signaling pathways, and proteasomeinhibition therefore appears to induce apoptosis through a number of mechanisms.
Our results indicate that both Bortezomib and BU-32 proteasomeinhibitors induce apoptosis in different breast cancer cells (MDA-MB-231, MCF7 and SKBR3).
Inhibition of the proteasome results in abnormal accumulation of many intracellular proteins, thereby disrupting cellular homeostasis , and results in the induction of tumor cell apoptosis .
The most studied and best characterized proteasomeinhibitor is Bortezomib (PS-341, Velcade®; Millenium Pharmaceuticals Inc., Cambridge, MA, USA and Johnson Pharmaceutical Research and Development, LLC, Raritan, NJ, USA), a dipeptide boronic acid that works by reversibly inhibiting the effects of the proteasome and inducing apoptosis in several tumor cell lines and animal models .
Inhibition of Notch signaling blocks cardiomyocyte proliferation and induces apoptosis. (A and B) DAPT treatment markedly suppresses both HES1- and CBF1-luciferase reporter activation.
The inhibition of Notch signaling in ICMs blocked their proliferation and induced apoptosis; in contrast, its activation by Jagged1 or by the constitutive expression of its activated form using an adeno-associated virus markedly stimulated proliferative signaling and promoted ICM expansion.
Knockdown of Bim dramatically inhibitedapoptosis induced by JAK2inhibition, which was reversed by the BH3 mimetic agent ABT-737.
In this study, we show that JAK2inhibition-induced apoptosis correlated with up-regulation of the nonphosphorylated form of the BH3-only protein Bim in hematopoietic cell lines bearing JAK2 mutations.
In addition, ABT-737 enhanced the apoptosis induced by JAK2inhibition in JAK2 V617F(+) HEL and SET-2 cells.
Inhibition of JAK2 activity leads to growth inhibition and apoptosis in cells with mutated JAK2.
It is also clear that down-regulation of active STAT3 is incompatible with the ALK-positive ALCL-transforming phenotype, as STAT3 compromised cells display increased apoptosis and cell-cycle arrest [,,,].
The observed interaction of NPM–ALK with JAK3, the receptor-associated tyrosine kinase responsible for STAT3 activation [,], provides a possible explanation for the effect of NPM–ALK on STAT3, given that inhibition of JAK3 leads to a reduction of STAT3 activation by NPM–ALK together with increased cellular apoptosis [,].
In agreement, ribozyme-mediated reduction of ALK in glioblastoma cell lines results in increased apoptosis [].
Inactivation of the PI3K pathway induces apoptosis in NPM–ALK-positive cells [,], indicating a role for the PI3K/PKB/Akt pathway in anti-apoptotic signalling.
Inhibition of proteasome function caused cell cycle arrest and apoptosis but this did not involve early activation of caspase-3.
Additionally, Wu and coworkers excluded the involvement of caspases in apoptosis of MO7e cells following proteasomeinhibition, as caspase inhibitorsfailed to prevent DNA fragmentation and it is therefore possible that proteasomeinhibition induces caspase-independent apoptosis as described for cells, defective in the ubiquitin pathway .
Apoptosis is regulated by the ubiquitin/proteasome system at various levels and inhibition of proteasome function may induce or preventapoptosis .
Since short-term proteasomeinhibition caused both apoptosis and radiosensitization in PC-3 cells, this model can be used to investigate the relationship between these phenomena and to explore the pathways that might interconnect them.
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