Caspase-9: structure, mechanisms and clinical application

Abstract

As the most intensively studied initiator caspase, caspase-9 is a key player in the intrinsic or mitochondrial pathway which is involved in various stimuli, including chemotherapies, stress agents and radiation. Caspase-9 is activated on the apoptosome complex to remain catalytic status and is thought of involving homo-dimerization monomeric zymogens. Failing to activate caspase-9 has profound physiological and pathophysiological outcomes, leading to degenerative and developmental disorders even cancer. To govern the apoptotic commitment process appropriately, plenty of proteins and small molecules involved in regulating caspase-9. Therefore, this review is to summarize recent pertinent literature on the comprehensive description of the molecular events implicated in caspase-9 activation and inhibition, as well as the clinical trials in progress to give deep insight into caspase-9 for suppressing cancer. We hope that our concerns will be helpful for further clinical studies addressing the roles of caspase-9 and its regulators demanded to identify more effective solutions to overcome intrinsic apoptosis-related diseases especially cancer.

Frataxin‐deficient neurons and mice models of Friedreich ataxia are improved by TAT‐MTScs‐FXN treatment

“…As shown in Figure C and D, addition of TAT‐MTScs‐FXN 7 μg/ml at 12 hrs after lentiviral transduction promotes optimal decrease in SBDPs as compared with results obtained by adding TAT‐MTScs‐FXN at 48 hrs. These results are also in agreement with those obtained by analysing caspase 9 activation, a marker of intrinsic or mitochondrial apoptotic pathway (for a review see ). In Figure E and F, reduced levels of the precursor form are observed in Fxn1 and Fxn2 cells, indicative of cleavage (activation) of this caspase.…”

Anticancer activity of a novel methylated analogue of L-mimosine against an in vitro model of human malignant melanoma

“…In addition, a more detailed characterization of various key proteins representative of the intrinsic and extrinsic apoptotic pathways was performed (by western immunoblotting) in A375 cells exposed to compound 22 (at 100 μM). The expression levels of cleaved and full length Caspase-8 were indicative of the involvement of the extrinsic apoptotic pathway [48][49][50][51] whereas those of Caspase-9 and Apoptotic protease-activating factor 1 (Apaf-1) for the intrinsic one [52][53][54][55]. In addition, expression levels of BID were reduced representative of the wellestablished interplay between the two apoptotic pathways [50].…”

Clerodane Diterpene Ameliorates Inflammatory Bowel Disease and Potentiates Cell Apoptosis of Colorectal Cancer

“…In general, an extrinsic apoptotic signaling pathway is started from the activation of death receptor (TRAIL receptor or TNF receptor) and terminated at pro-caspase-3 cleavage via caspase-8 activation [29,30]. Different from extrinsic apoptosis, intrinsic apoptotic signaling is mediated by Bcl-2 to cause the loss of mitochondrial membrane potential or growth signaling depletion, which leads to cytochrome c release, pro-caspase-9 cleavage, and consequently, caspase-3 activation [29,31,32]. Therefore, by observing the altered levels of cleavage caspase-8, caspase-9, and Bcl-2, the type of chemical-induced apoptosis could be putatively addressed.…”