Cardiotoxin III‐induced apoptosis is mediated by Ca²⁺‐dependent caspase‐12 activation in K562 cells

Abstract

Cardiotoxin III (CTX III), a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom, has been reported to have anticancer activity. When K562 cells were treated with CTX III, cytosolic calcium concentration was rapidly and persistently increased. This CTX III-induced cell death was partially reversed by pretreatment with BAPTA/AM (20 microM), a chelator of intracellular Ca2+. Moreover, CTX III-induced apoptotic signals, such as caspase-12 and c-Jun N-terminal kinase (JNK) activation, were induced in a time-dependent manner and inhibited by BAPTA/AM. In contrast, the neutral protease micro-calpain, a key enzyme in endoplasmic reticulum (ER) stress-related apoptosis via caspase-12 activation, was unchanged during apoptosis. Taken together, our findings suggest CTX III-induced apoptosis is triggered by Ca2+ influx, then activated caspase-12 and JNK through micro-calpain-independent cascade, and consequently caused apoptosis.

Cleavage of caspase‐12 at Asp94, mediated by endoplasmic reticulum stress (ERS), contributes to stretch‐induced apoptosis of myoblasts

“…One plausible interpretation is that mechanical overloading triggered ERS in myoblast through other mechanisms independently of calcium homeostasis, thus had little effect on calpain activation. Another possibility is that calpain could stay inactivated even when intracellular calcium concentration is high, reported by Yang, Chien, Chang, & Lin (). Besides, we do not deny that calpain might be activated and cleave caspase‐12 during stretch loading for less than 12 hr, as demonstrated by Martinez et al () that calpain preceded caspase‐7 in cleaving caspase‐12 during ERS.…”

In Vitro Cytotoxic and Proapoptotic Activities of Anatolian Macrovipera Lebetina Obtusa (Dwigubski, 1832) Crude Venom on Cultured K562 Human Chronic Myelogenous Leukemia Cells.

“…Number of described snake venom proteins, including metalloproteinase, disintegrin, CLP, PLA 2 and LAAO, purified from the venom of different species have been shown to induce apoptosis interacting different pathways. 12,[17][18][19][20][21][22]40 In the present study, preliminary information showing the induction of apoptosis in K562 cells after exposure to M. lebetina obtusa venom was obtained by the observation of the morphological characteristics of apoptosis as well as activation of caspase-3 by immunohistochemistry. Caspase-3 is one of the key executioners of apoptosis.…”

“…32,33 There are limited studies investigating the induction of apoptosis in K562 cells, after treatment with crude snake venom or purified proteins. 14,17,19,22,38,[41][42][43] Samel et al 19 investigated the effect of Sephadex G-100 chromatography fractions of M. lebetina turanica (subspecies was not mentioned in the paper but assigned according to the locality) venom and also purified HUVEC apoptosis inducing metalloproteinase (VLAIP). The first fraction reported to inhibit the viability of K562 cells about 30%.…”

“…41 According to these results, the authors suggested that cardiotoxin III induced apoptosis in K562 cells through ROS-independent mitochondrial dysfunction pathway. Yang et al 22 showed that cardiotoxin III-induced apoptosis was mediated by Ca 2+ -dependent caspase-12 activation in K562 cells. PLA 2 and LAAO from the venom of Vipera berus berus also showed proapoptotic effect on K562 cells.…”

Anticancer Activity of Toxins from Bee and Snake Venom—An Overview on Ovarian Cancer

“…The mechanism through which cardiotoxin-3 (CTX-3) from Naja naja atra venom exercises its effects on tumors was studied by Yang et al [ 89 ] who reported that apoptosis is followed by increased expression of Bax and endonuclease G and decreased expression of Bcl-x in K562 cells. Another report showed that CTX-3 possesses apoptotic effects through the activation of the JNK pathway and caspase-12 by triggering Ca 2+ influx, the consequence being the rapid increase in the cytosolic Ca 2+ concentration [ 90 ].…”