Bcl-2 family members are important regulators of cell survival and cell death. Researchers have focused mainly on mitochondria, where both proapoptotic and antiapoptotic family members function to regulate the release of cytochrome c and other mediators of apoptosis. However, as reviewed here, Bcl-2 family members also operate on another front, the endoplasmic reticulum (ER), to both positively and negatively regulate the release of Ca2+. There is abundant evidence that Ca2+ signals trigger apoptosis in response to a wide variety of agents and conditions. Conversely, Ca2+ signals can also mediate cell survival. Recent findings indicate that Bcl-2 interacts with inositol 1,4,5-trisphosphate (IP3) receptor Ca2+ channels on the ER, regulating their opening in response to IP3- and thus inhibiting IP3-mediated Ca2+ signals that induce apoptosis while enhancing Ca2+ signals that support cell survival.
"First, the metabolic rewiring of neoplastic cells should not be considered as a self-standing hallmark of malignancy, but rather as a phenomenon that intimately accompanies, allows for and cannot be mechanistically separated from many, if not all, aspects of oncogenesis (Galluzzi et al., 2013; Locasale & Cantley, 2011; Wellen & Thompson, 2012). Accumulating evidence indicates indeed that (1) several metabolic intermediates such as ATP, acetyl-CoA, a-ketoglutarate, and reactive oxygen species play a major role in cell-intrinsic as well as cell-extrinsic signaling pathways (Galluzzi, Kepp, & Kroemer, 2012; Locasale & Cantley, 2011; Wellen & Thompson, 2012); (2) multiple proteins with prominent metabolic functions such as cytochrome c (which operates as an electron shuttle in the mitochondrial respiratory chain) and the M2 isoform of pyruvate kinase (PKM2, which catalyzes the last step glycolysis) participate in signal transduction (Galluzzi, Kepp, & Kroemer, 2012; Galluzzi, Kepp, Trojel-Hansen, & Kroemer, 2012; Gao, Wang, Yang, Liu, & Liu, 2012; Luo et al., 2011; Yang et al., 2011); and (3) several proteins initially viewed as " pure " signal transducers including (but not limited to) the antiapoptotic Bcl-2 family members BCL-X L and MCL1 also impact on metabolic functions such as the handling of Ca 2+ ions at the endoplasmic reticulum and the enzymatic activity of the F 1 F 0 ATP synthase (Alavian et al., 2011; Perciavalle et al., 2012; Rong & Distelhorst, 2008). "
"Bcl-2 is originally found in a translocation chromosomal fragment in B-cell lymphoma and is proved as a protooncogene . The members of Bcl-2 family all contain a BH (Bcl-2 homology) domain structure and are divided into two major groups: one composed of antiapoptotic molecules, including Bcl-2, Bcl-xL, Bcl-w, Mcl-1, Boo/Diva, and A1/Bfl- 1  and the other comprises proapoptotic molecules, such as Bax, Bak, Bad, Bim, Bik, PUMA, and NOXA . Under normal conditions, the Bcl-2 or Bcl-xL complexes with Bax or Bak to form homo-or hetero dimer, and such interaction will neutralize proapoptotic molecules to prevent cell death. "
[Show abstract][Hide abstract] ABSTRACT: Destruxin B, isolated from entomopathogenic fungus Metarhizium anisopliae, is one of the cyclodepsipeptides with insecticidal and anticancer activities. In this study, destruxin B was extracted and purified by ion-exchange chromatography, silica gel chromatography, and semipreparative high-performance liquid chromatography. The potential anticancer effects and molecular mechanisms of destruxin B in human nonsmall cell lung cancer cell lines were characterized. Our results showed that destruxin B induced apoptotic cell death in A549 cells. This event was accompanied by the activation of caspase-2, -3, and -9. Moreover, destruxin B increased the expression level of proapoptotic molecule, PUMA, while decreased antiapoptotic molecule Mcl-1. Additionally, the translocation of Bax from cytosol to mitochondrial membrane was observed upon destruxin B treatment. Knockdown of Bax by shRNA effectively attenuated destruxin-B-triggered apoptosis in A549 cells. Interestingly, similar toxic effects and underlying mechanisms including caspase activation, upregulation of PUMA, and downregulation of Mcl-1 were also observed in a p53-null lung cancer H1299 cell line upon destruxin B treatment. Taken together, our findings suggest that destruxin-B-induced apoptosis in human nonsmall cell lung cancer cells is via a Bcl-2 family-dependent mitochondrial pathway.
Evidence-based Complementary and Alternative Medicine 09/2013; 2013:548929. DOI:10.1155/2013/548929 · 1.88 Impact Factor
"We hypothesized that, through signaling interactions with the mitochondria, the ER would actively participate in regulating the homeostasis of sonoporated cells. This hypothesis is formulated on the basis earlier observations by us (Zhong et al. 2011) and others (Kinoshita et al. 2007) that sonoporation would disrupt the baseline expression level of a cell's Bcl-2 (B cell lymphoma-2) signaling protein family: a specialized class of messenger proteins that are known to interact closely with ER and mitochondria in regulating cell viability (Rong and Distelhorst 2008). In terms of its significance, our investigation was intended to bolster current scientific understanding on the complexity of sonoporation-induced bio-effects. "
[Show abstract][Hide abstract] ABSTRACT: The use of cavitational means to create transient membrane pores on living cells (i.e., sonoporation) may potentially induce a broad range of downstream bio-effects that disrupt the functioning of various organelles. Here we observed that on HL-60 leukemia cells, sonoporation may induce endoplasmic reticulum (ER) stress on a time-lapse basis and, in turn, signal the mitochondria to commit a cell toward apoptosis. Our observations were derived from in vitro ultrasound exposure experiments performed on HL-60 cells in the presence of lipid-shelled microbubbles (1:1 cell-to-bubble ratio; 1-MHz frequency; 0.45-MPa in situ peak negative pressure; 100-cycle pulse length; 1-kHz pulse repetition frequency; 60-s exposure period). Using flow cytometry, we found that sonoporated cells exhibited a progressive loss of functional ER mass over a 6-h period. Also, post-exposure Western blot assays (between 0 and 24 h) revealed various indications of post-sonoporation ER stress: (i) upregulation of ER-resident enzymes responsible for catalyzing protein folding; (ii) activation of trans-ER-membrane stress sensors; (iii) increased expression of ER-induced regulatory proteins that mediate pro-apoptotic signals to the mitochondria. These results corresponded to flow cytometry observations that depicted a progressive depolarization of a sonoporated cell's mitochondrial outer membrane potential. They were also consistent with another Western blot assay that found, in sonoporated cells, a time-lapse increase of caspase-9 (a mitochondria-activated apoptosis initiator protein). Taken together, our findings indicate that sonoporation may upset ER homeostasis, and this may ultimately result in initiation of apoptosis.
Ultrasound in medicine & biology 09/2013; 39(12). DOI:10.1016/j.ultrasmedbio.2013.08.005 · 2.21 Impact Factor
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