By a News Reporter-Staff News Editor at Gene Therapy Weekly -- Current study results on Biotechnology have been published. According to news reporting out of Thiruvananthapuram, India, by NewsRx editors, research stated, "Procaspase-activating compound-1 (PAC-1) is the first direct caspase-activating compound discovered; using an in vitro cell-free system of caspase activation. Subsequently, this compound was shown to induce apoptosis in a variety of cancer cells with promising in vivo antitumor activity in canine lymphoma model."
Our news journalists obtained a quote from the research from Rajiv Gandhi Center for Biotechnology, "Recently, we have reported its ability to kill drug-resistant, Bcl-2/Bcl-xL overexpressing and Bax/Bak-deficient cells despite the essential requirement of mitochondrial cytochrome c (cyt. c) release for caspase activation, indicating that the key molecular targets of PAC-1 in cancer cells are yet to be identified. Here, we have identified Ero1 alpha-dependent endoplasmic reticulum (ER) calcium leakage to mitochondria through mitochondria-associated ER membranes (MAM) and ER luminal hyper-oxidation as the critical events of PAC-1-mediated cell death. PAC-1 treatment upregulated Ero1 alpha in multiple cell lines, whereas silencing of Ero1 alpha significantly inhibited calcium release from ER and cell death. Loss of ER calcium and hyper-oxidation of ER lumen by Ero1 alpha collectively triggered ER stress. Upregulation of GRP78 and splicing of X-box-binding protein 1 (XBP1) mRNA in multiple cancer cells suggested ER stress as the general event triggered by PAC-1. XBP1 mRNA splicing and GRP78 upregulation confirmed ER stress even in Bax/Bak double knockout and PAC-1-resistant Apaf-1-knockout cells, indicating an induction of ER stress-mediated mitochondrial apoptosis by PAC-1. Furthermore, we identified BH3-only protein p53 upregulated modulator of apoptosis (PUMA) as the key molecular link that orchestrates overwhelmed ER stress to mitochondria-mediated apoptosis, involving mitochondrial reactive oxygen species, in a p53-independent manner."
According to the news editors, the research concluded: "Silencing of PUMA in cancer cells effectively reduced cyt. c release and cell death by PAC-1."
For more information on this research see: ERO1 alpha-dependent endoplasmic reticulum-mitochondrial calcium flux contributes to ER stress and mitochondrial permeabilization by procaspase-activating compound-1 (PAC-1). Cell Death & Disease, 2013;4():294-307. Cell Death & Disease can be contacted at: Nature Publishing Group, Macmillan Building, 4 Crinan St, London N1 9XW, England. (Nature Publishing Group - www.nature.com/; Cell Death & Disease - www.nature.com/cddis/)
Our news journalists report that additional information may be obtained by contacting M. Seervi, Rajiv Gandhi Center Biotechnol, Canc Res Program 1, Thiruvananthapuram 695014, Kerala, India. Additional authors for this research include P.K. Sobhan, J. Joseph, K.A. Mathew and T.R. Santhoshkumar (see also Biotechnology).
Keywords for this news article include: Asia, Biotechnology, India, Caspases, Genetics, Oncology, p53 Gene, Apoptosis, Cytoplasm, Organelles, Mitochondria, Thiruvananthapuram, Peptide Hydrolases, Cancer Gene Therapy, Cellular Structures, Intracellular Space, Endoplasmic Reticulum, Enzymes and Coenzymes, Subcellular Fractions, Cysteine Endopeptidases
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