Calcium‐stimulated mitogen‐activated protein kinase activation elicits Bcl‐xL downregulation and Bak upregulation in notexin‐treated human neuroblastoma SK‐N‐SH cells

Abstract

Notechis scutatus scutatus notexin induced apoptotic death of SK-N-SH cells accompanied with downregulation of Bcl-xL, upregulation of Bak, mitochondrial depolarization, and ROS generation. Upon exposure to notexin, Ca(2+)-mediated JNK and p38 MAPK activation were observed in SK-N-SH cells. Production of ROS was a downstream event followed by Ca(2+)-mediated mitochondrial alteration. Notexin-induced cell death, mitochondrial depolarization, and ROS generation were suppressed by SB202190 (p38 MAPK inhibitor) and SP600125 (JNK inhibitor). Moreover, phospho-p38 MAPK and phospho-JNK were proved to be involved in Bcl-xL degradation, and overexpression of Bcl-xL attenuated the cytotoxic effect of notexin. Bak upregulation was elicited by p38 MAPK-mediated ATF-2 activation and JNK-mediated c-Jun activation. Suppression of Bak upregulation by ATF-2 siRNA or c-Jun siRNA attenuated notexin-evoked mitochondrial depolarization and rescued viability of notexin-treated cells. Taken together, our data indicate that notexin-induced apoptotic death of SK-N-SH cells is mediated through mitochondrial alteration triggering by Ca(2+)-evoked p38 MAPK/ATF-2 and JNK/c-Jun signaling pathways.

Quinacrine induces apoptosis in human leukemia K562 cells via p38 MAPK-elicited BCL2 down-regulation and suppression of ERK/c-Jun-mediated BCL2L1 expression

“…Measurement of caspase-3/-8/-9 activity, detection of apoptotic cells using annexin V/propidium iodide staining and Western blot analyses were performed in essentially the same manner as previously described (Liu and Chang, 2009;Chen et al, 2010;Chen and Chang, 2014).…”

“…Following induction of apoptosis, cytosolic and pellet (mitochondrial) fractions were generated using a digitonin-based subcellular fractionation technique according to the method described in Chen et al (2010). Cytochrome c and BAX were detected by Western blot analysis.…”

Inhibition of PP2A and the consequent activation of JNK/c‐Jun are involved in tributyltin‐induced apoptosis in human amnionic cells

“…It has been widely accepted that a higher Bax/Bcl‐2 ratio alters mitochondrial permeability and ΔΨm to activate caspase‐3, which, in turn, induces apoptosis. Several studies have suggested that JNK and p38 may be the upstream signals of the Bax/Bcl‐2‐evoked mitochondrial apoptosis pathway (Kang and Lee,2008 ; Su et al,2009; Chen et al,2010b ; Deng et al,2010). Our previous study showed that Bax/Bcl‐2 ratio elevation and caspase‐3 activation were both detected synchronously with apoptosis in TBT‐treated human amnion cells (Zhu et al,2007).…”

ATF2 (activating transcription factor 2)

“…Apoptosis ATF2/CREB1 heterodimer binds to the CRE element of the BCL2 promoter . ATF2 induces BAK upregulation (Chen et al, 2010). MAP3K5 (ASK1) activates ATF2 and FADD-CASP8-BID signalling, resulting in the translocation of BAX and BAK, and subsequently mitochondrial dysregulation (Hassan et al, 2009).…”