3.ALPHA.,23-Isopropylidenedioxyolean-12-en-27-oic Acid, a Triterpene Isolated from Aceriphyllum rossii, Induces Apoptosis in Human Cervical Cancer HeLa Cells through Mitochondrial Dysfunction and Endoplasmic Reticulum Stress

Abstract

Despite of the widespread use of the Papanicolaou smear and HPV (human papollomavirus) vaccine, cervical cancer remains the most common cancer in women under 45 years of age in developing countries. Furthermore, almost half of all women with invasive cervical cancer are diagnosed at a late stage. Accordingly, there is an urgent need to identify an agent that can be used alone or in combination with a conventional anti-cancer drug like cisplatin, to improve the prognosis of this disease. 1)Apoptosis, a morphologically and biochemically defined form of cell death, plays a key role in the regulation of the growth of normal and neoplastic tissues.2) Recent studies have amply documented that two major pathways are involved in the regulation of apoptosis. The extrinsic apoptotic pathway involves cell surface death receptors such as Fas/CD95 and tumor necrosis factor receptor 1, 2 (TNFR1, 2), which upon activation up-regulate downstream signaling cascade including the activation of caspase-8.2) The intrinsic pathway is dependent on various cell stress stimuli leading to altered ratio of Bcl-2 family members affecting the release of cytochrome c and apoptotic protease activating factor-1 (Apaf-1) that leads to caspase-9 activation.3) The active forms of caspase-8 and -9 may activate downstream effector caspases-3, -6, and -7, resulting in the cleavage of several intracellular polypeptides (e.g., PARP-1) as well as activation of DNase that leads to DNA fragmentation.Endoplasmic reticulum (ER) is a central organelle engaged in lipid synthesis and protein folding and maturation. A variety of toxic insults, including failure of protein synthesis, folding, and degradation and Ca 2ϩ overload, can disturb the ER function and result in ER stress. 4,5) Under normal conditions, the ER stress sensors (IRE1, PERK, and ATF6) reside with binding to glucose-regulated protein 78 (GRP78). When ER stress occurred, the sensors dissociate with GRP78 and transfer downstream signals to the cytoplasm. As a consequence, these compensatory responses contribute to the reduction of ER overload and functions to protect cells against ER stress. However, if the ER functions are severely affected, cells are removed by apoptosis. ER stress-mediated apoptosis is triggered by the activation of ER membrane resident caspase-12 and induction of growth arrest DNA damageinducible gene 153 (GADD153).6,7) Calpains (a family of Ca 2ϩ -dependent intracellular cysteine proteases) are also implicated in ER stress-induced apoptosis. There are ubiquitously expressed calpain I (m-calpain) and calpain II (m-calpain) proteases. A recent study has shown that ubiquitous calpains promote caspase-12 and c-Jun N-terminal kinase (JNK) activation during ER stress-induced apoptosis. 8)Numerous naturally occurring substances are recognized to be anti-oxidants, cancer preventive agents, or even antitumor agent such as paclitaxel.9) Triterpenes are part of a family of naturally occurring compounds and present a wide spectrum of pharmacological activities, with one of the most elu...

Calcium efflux from the endoplasmic reticulum regulates cisplatin-induced apoptosis in human cervical cancer HeLa cells

“…It is reported that the overexpression of calpains promotes the cleavage of Bid, which in turn modulates Bax and activates caspase-3. There is also evidence to suggest that activation of caspase-4 requires calpains ( 38 – 40 ). The aforementioned results suggest that calcium signaling involves two apoptotic pathways: i) Calcium ion entry into the mitochondria, which induces calcium disorder in he mitochondria and leads to mitochondria-mediated apoptosis; and ii) calcium signaling in the cytosol activates calcium-dependent proteases and results in the expression of ER stress-associated apoptotic proteins.…”

“…To investigate this hypothesis, the calcium chelating agent, BAPTA/AM, was used to block free Ca 2+ in the cytoplasm. Won et al reported that apoptosis induced by 3α,23-isopropylidenedioxyolean-12-en-27-oic acid was substantially reduced following combined treatment with BAPTA/AM in HeLa cells ( 40 ). In the present study, HeLa cells were treated with cisplatin combined with BAPTA/AM.…”

2,3,5,4′‐tetrahydroxystilbene‐2‐O‐β‐d‐glucoside protects human umbilical vein endothelial cells against lysophosphatidylcholine‐induced apoptosis by upregulating superoxide dismutase and glutathione peroxidase

“…There are three apoptotic pathways: cell surface death receptors‐Caspase‐8‐Caspase‐3 ; mitochondria/MMP‐Cyt C‐Caspase‐9‐Caspase‐3 ; endoplasmic reticulum/Ca 2+ ‐Caspase‐12‐Caspase‐3 . The three apoptotic cascades converge on the activation of caspase‐3, which results in the cleavage of intracellular poly (ADP ribose) polymerase (PARP‐1) and the activation of DNase, leading to DNA fragmentation . Bcl‐2 family members play important roles in mitochondria‐dependent activation of caspase cascades .…”

Transcriptomic and proteomic insight into the effects of a defined European mistletoe extract in Ewing sarcoma cells reveals cellular stress responses

“…Notably, viscumTT and viscum treatment concurrently displayed a decrease of EIF2AK3, whereas TT treatment showed a slight upregulation matching ER stress. Others demonstrated the induction of apoptosis by ER stress in HeLa cells after treatment with an oleanolic acid derivative [73]. Proteomic investigation of betulinic acid-induced apoptosis in HeLa cells also displayed the induction of ER stress [74].…”