The hsp70 inhibitor VER155008 induces paraptosis requiring de novo protein synthesis in anaplastic thyroid carcinoma cells

Jiang

et al. 2015

IJMS

8-p-Hdroxybenzoyl tovarol (TAW) is a germacrane-type sesquiterpenoid that can be isolated from the roots of Ferula dissecta (Ledeb.) Ledeb. In this study, the growth inhibitory effects induced by TAW were screened on some types of tumor cells, and the mechanism was investigated on TAW-induced growth inhibition, including paraptosis and autophagy in human cervical cancer HeLa cells. TAW-induced paraptosis involved extensive cytoplasmic vacuolization in the absence of caspase activation. Additionally, TAW evoked cell paraptotic death mediated by endoplasmic reticulum (ER) stress and unfolded protein response (UPR). Autophagy induced by TAW was found to antagonize paraptosis in HeLa cells. This effect was enhanced by rapamycin and suppressed by the autophagy inhibitor, 3-methyladenine (3MA). Loss of beclin 1 (an autophagic regulator) function led to promote ER stress. Taken together, these results suggest that TAW induces paraptosis like cell death and protective autophagy in HeLa cells, which would provide a new clue for exploiting TAW as a promising agent for the treatment of cervical cancer.

Section: Methodsmentioning

confidence: 99%

8-p-Hdroxybenzoyl Tovarol Induces Paraptosis Like Cell Death and Protective Autophagy in Human Cervical Cancer HeLa Cells

Jiang

et al. 2015

IJMS

“…In addition to geldanamycin and Velcade, PLCD and ER vacuolization can be triggered by inhibitor of HSP70 VER155008 [81], other ERAD inhibitors (e.g., thioxotriazole or phosphine copper complexes [15, 82], gold complexes [83]), proteasome inhibitors MG-132, lactalysin, and tunicamycin [79, 80], as well as a number of compounds not directly interacting with ERAD components. The latter can be conventionally divided into two groups.…”

Section: Vacuolization and Known Cell Death Pathwaysmentioning

confidence: 99%

Cytoplasmic vacuolization in cell death and survival

et al. 2016

Cytoplasmic vacuolization (also called cytoplasmic vacuolation) is a well-known morphological phenomenon observed in mammalian cells after exposure to bacterial or viral pathogens as well as to various natural and artificial low-molecular-weight compounds. Vacuolization often accompanies cell death; however, its role in cell death processes remains unclear. This can be attributed to studying vacuolization at the level of morphology for many years. At the same time, new data on the molecular mechanisms of the vacuole formation and structure have become available. In addition, numerous examples of the association between vacuolization and previously unknown cell death types have been reported. Here, we review these data to make a deeper insight into the role of cytoplasmic vacuolization in cell death and survival.

“…Paraptosis is characterized by cytoplasmic vacuolation that could be generated from swelling of the endoplasmic reticulum and/or mitochondria. The paraptosis usually does not have caspase activation an apoptotic hallmark [ 5 , 6 ]. Moreover, there is evidence that a protein synthesis inhibitor cycloheximide (CHX) can block the formation of cytoplasmic vacuole in cytoplasmic vacuolation-mediated cell death and paraptosis [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Xanthohumol induces paraptosis of leukemia cells through p38 mitogen activated protein kinase signaling pathway

Wang

Sun

et al. 2017

Oncotarget

Xanthohumol as a natural polyphenol demonstrates an anticancer activity, but its underlying mechanism remains unclear. In this study, we showed that xanthohumol (XN) induces paraptosis of leukemia cells. The paraptosis is one cell death which is characterized by dilation of the endoplasmic reticulum and/or mitochondria. The results demonstrated that XN treatment significantly inhibited cell proliferation and triggered extensive cytoplasmic vacuolation of HL-60 leukemia cells, but it did not cause the cleavage of caspase-3 protein or apoptosis. In contrast, XN treatment resulted in LC3-II accumulation through blocking of autophagosome maturation. Interestingly, the induction of cytoplasmic vacuolization by XN is not associated with autophagy modulated by XN, therefore, XN-induced cell death of HL-60 leukemia cells is not the classical apoptotic cell death. Intriguingly, XN treatment triggered the dilatation of endoplasma reticulum (ER) and induced ER stress by upregulating C/EBP homologous protein and unfolded protein response regulator Grp78/Bip. Furthermore, XN treatment triggered p38 mitogen activated protein kinase and its specific inhibitor inhibited the paraptosis of HL-60 leukemia cells by XN. In conclusion, we for the first time demonstrated that XN treatment can induce paraptosis of leukemia cells through activation of p38 MAPK signaling.