Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P11021 (BiP)
 2,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA damage is believed to be the main cause of the antiproliferative effect of cisplatin, a cornerstone agent in anticancer therapy. However, cisplatin can be expected to react also with nucleophiles other than DNA. Using enucleated cells (cytoplasts) we demonstrate here that cisplatin-induced apoptotic signaling may occur independently of DNA damage. Cisplatin-induced caspase-3 activation in cytoplasts required calcium and the activity of the calcium-dependent protease calpain. It is known that calpain activation may be associated with endoplasmic reticulum (ER) stress, suggesting that the ER is a cytosolic target of cisplatin. Consistent with this hypothesis, cisplatin induced calpain-dependent activation of the ER-specific caspase-12 in cytoplasts as well as in intact cells. Cisplatin also induced increased expression of Grp78/BiP, another marker of ER stress. By contrast, the DNA-damaging topoisomerase II inhibitor etoposide did not induce apoptotic signaling in cytoplasts nor ER stress in intact cells. We have thus identified a novel mechanism of action of cisplatin. The results have implications for the understanding of resistance mechanisms as well as the unique efficiency of this drug.
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PMID:Cisplatin induces endoplasmic reticulum stress and nucleus-independent apoptotic signaling. 1250 15

Anticancer drugs often show complex mechanisms of action, including effects on multiple cellular targets. Detailed understanding of these intricate effects is important for the understanding of cytotoxicity. In this study, we examined apoptosis induction by ellipticines, a class of cytotoxic plant alkaloids known to inhibit topoisomerase II. The potent ellipticine derivative 6-propanamine ellipticine (6-PA-ELL) induced rapid apoptosis in MDA-MB-231 breast cancer cells, preceded by a conformational change in Bak and cytochrome c release. Experiments using knock-out mouse embryo fibroblasts established that Bak was of particular importance for cytotoxicity. 6-PA-ELL increased the expression of the endoplasmic reticulum chaperones GRP78/BiP and GRP94, suggesting induction of endoplasmic reticulum stress. Induction of GRP78 expression was dependent on the endoplasmic reticulum stress response element (ERSE) of the GRP78 promoter. Examination of different ellipticine derivatives revealed a correlation between pro-apoptotic activity and the ability to induce GRP78 expression. Furthermore, 6-PA-ELL was found to induce splicing of the mRNA encoding the XBP1 transcription factor, characteristic of endoplasmic reticulum stress, and to induce activation of the endoplasmic reticulum-specific caspase-12 in mouse colon cancer cells. We finally demonstrate that 6-PA-ELL induces apoptotic signaling also in enucleated cells, consistent with the existence of a cytoplasmic target for this compound. Our data suggest that induction of endoplasmic reticulum stress may contribute to the cytotoxicity of ellipticines.
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PMID:Induction of endoplasmic reticulum stress by ellipticine plant alkaloids. 1507 93

A wide range of chemotherapeutic agents has been identified that are active against solid tumors. However, resistance remains an important obstacle to the development of curative regimens. Whereas much attention has been paid to acquired drug resistance, a variety of physiological pathways also have been described that reduce the sensitivity of previously untreated tumors to cytotoxic antitumor agents. Treatment of cells with pharmacological agents that alter the environment of the endoplasmic reticulum (ER) and activate the unfolded protein response (UPR) can render cells resistant to topoisomerase II poisons. We describe experiments showing that activation of the mammalian ER stress response is both necessary and sufficient to decrease topoisomerase IIalpha protein levels and to render cells resistant to etoposide, a topoisomerase II-targeting drug. This is not caused by the elevated levels of BiP that are a hallmark of this response, because a cell line that has been engineered to overexpress BiP does not show increased resistance to etoposide. The UPR was shown to be required for altered drug sensitivity, because the BiP-overexpressing cell line, which is unable to activate the UPR, did not show decreased topoisomerase II levels or increased resistance to etoposide in response to stress conditions. The transient overexpression of an unfolded protein activated the UPR and led to the concomitant loss of topoisomerase IIalpha protein from the cells, demonstrating that UPR activation is sufficient for the changes in topoisomerase II levels that had been observed previously with pharmacological induction of the UPR.
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PMID:Activation of the unfolded protein response is necessary and sufficient for reducing topoisomerase IIalpha protein levels and decreasing sensitivity to topoisomerase-targeted drugs. 1614 12