Snake venom toxin from vipera lebetina turanicainduces apoptosis of colon cancer cells via upregulation of ROS- and JNK-mediated death receptor expression

Abstract

BackgroundAbundant research suggested that the cancer cells avoid destruction by the immune system through down-regulation or mutation of death receptors. Therefore, it is very important that finding the agents that increase the death receptors of cancer cells. In this study, we demonstrated that the snake venom toxin from Vipera lebetina turanica induce the apoptosis of colon cancer cells through reactive oxygen species (ROS) and c-Jun N-terminal kinases (JNK) dependent death receptor (DR4 and DR5) expression.MethodsWe used cell viability assays, DAPI/TUNEL assays, as well as western blot for detection of apoptosis related proteins and DRs to demonstrate that snake venom toxin-induced apoptosis is DR4 and DR5 dependent. We carried out transient siRNA knockdowns of DR4 and DR5 in colon cancer cells.ResultsWe showed that snake venom toxin inhibited growth of colon cancer cells through induction of apoptosis. We also showed that the expression of DR4 and DR5 was increased by treatment of snake venom toxin. Moreover, knockdown of DR4 or DR5 reversed the effect of snake venom toxin. Snake venom toxin also induced JNK phosphorylation and ROS generation, however, pretreatment of JNK inhibitor and ROS scavenger reversed the inhibitory effect of snake venom toxin on cancer cell proliferation, and reduced the snake venom toxin-induced upregulation of DR4 and DR5 expression.ConclusionsOur results indicated that snake venom toxin could inhibit human colon cancer cell growth, and these effects may be related to ROS and JNK mediated activation of death receptor (DR4 and DR5) signals.

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.…”

“…Furthermore, venoms or purified proteins from different subspecies of M. lebetina also induced apoptosis in other various cancers and non-cancerous cells, through different mechanisms. 18,20,21,44 Sanz et al 45 identified PLA2, LAAO, metalloproteinase, serine proteinase, natriuretic peptide, disintegrin, BPP and CRISP protein families in the venom of M. l. obtusa from Armenia by mass spectrometry-based proteomics approach. Igci and Demiralp 8 reported the similar protein content with additions of NGF, VEGF and protease inhibitor for Anatolian M. l. obtusa.…”

Propensity of crocin to offset Vipera russelli venom induced oxidative stress mediated neutrophil apoptosis: a biochemical insight

“…The interplay between oxidative stress and inflammation has been implicated in the pathophysiology of many diseases including cardiovascular diseases, diabetes, cancer, arthritis, chronic kidney and neurological diseases. Several studies have demonstrated that the snake venom and their isolated components such as PLA 2 and metalloproteases induce apoptosis in different cell types (Valko et al 2007;Brenes et al 2010;Murakami et al 2011;Park et al 2012). Venom induced cell death is currently the subject of considerable interest for toxicologists in order to understand the molecular mechanism and to explore the possible therapeutic purposes of venom.…”

“…Some of the studies have also shown the inhibition of venom induced apoptosis by using antioxidant enzymes. Our previous study has also shown the protective role of crocin against viper venom induced apoptosis of platelets (Torii et al 1997;Kumar et al 2002;Park et al 2012;Liu and Chang 2009;Santhosh et al 2013b).…”

“…Venom induced cell death is currently the subject of considerable interest for toxicologists in order to understand the molecular mechanism and to explore the possible therapeutic purposes of venom. Snake venoms can activate apoptosis either through extrinsic pathway by triggering the binding of extracellular death ligand to the transmembrane death receptors, such as the Fas receptors (Díaz et al 2005) or through intrinsic pathway initiated by cellular stress, specifically mitochondrial oxidative stress caused by factors such as DNA damage and heat shock (Park et al 2012;Liu and Chang 2009).…”