Inactivation of prosurvival Bcl-2 proteins activates Bax/Bak through the outer mitochondrial membrane

O’Neill, Katelyn; Huang, Kai; Zhang, Jingjing; Chen, Yi; Luo, Xu

doi:10.1101/gad.276725.115

Cited by 269 publications

(274 citation statements)

References 63 publications

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“…As the main members of the Bcl-2 family, Bcl-2, Bax and Bcl-xL mainly regulate the apoptosis of cells by affecting the mitochondrial pathway. When cells receive death signals, Bax, which is bound to Bcl-2 or Bcl-xL, is displaced, increasing the permeability of the mitochondrial membrane and leading to the release of a series of substances, thus eventually causing the death of cells (19).…”

Section: Discussionmentioning

confidence: 99%

Lactobacillus raises in vitro anticancer effect of geniposide in HSC‑3 human oral squamous cell carcinoma cells

Zhou

Wang

et al. 2017

Exp Ther Med

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Abstract. The present study determined the ability of the Lactobacillus rhamnosus GG strain (LGG) to enhance the anticancer effects of geniposide on HSC-3 human oral squamous carcinoma cells.LGG (1.0x10 3 CFU/ml) on its own had no impact on human oral keratinocytes and HSC-3 cancer cells. Geniposide (25 or 50 µg/ml) had no impact on human oral keratinocytes, but exerted growth inhibitory effects on HSC-3 cancer cells, which were increased in the presence of LGG. Flow cytometric analysis and a nuclear staining assay with DAPI revealed that HSC-3 cancer cells treated with LGG-geniposide (1.0x10 3 CFU/ml LGG and 50 µg/ml geniposide) had a higher apoptotic rate than cells in other treatment groups, particularly that treated with geniposide (50 µg/ml) only. Geniposide also increased the mRNA and protein expression of caspase-3, -8 and -9 as well as B-cell lymphoma 2 (Bcl-2)-associated X protein, p53, p21, inhibitor of nuclear factor-κB (NF-κB) α, Fas and Fas ligand, while decreasing Bcl-2, Bcl extra large protein, inhibitor of apoptosis-1 and -2, NF-κB, cyclooxigenase-2 and inducible nitric oxide synthase in HSC-3 cells, which was increased in the presence of LGG. These results indicated that LGG enhanced the anticancer effects of geniposide in HSC-3 cells. IntroductionGardenia jasminoides Ellis belongs to the Rubiaceae family and Gardenia genus, and its dried ripe fruit can be used as a medicine, with bitter and cold taste, and nourishing the heart, lungs and San Juao meridian according to the principles of Chinese Medicine (1). Gardenia fruit mainly protects the liver and nourishes the gallbladder, and its active constituent is geniposide, which belongs to the iridoid glycosides (2). It is also rich in other constituents such as organic acids, pigments and volatile oils (3). A pharmacokinetic study has found that geniposide, the active constituent of Gardenia jasminoides Ellis, is hydrolyzed by β-glucosidase produced by intestinal microorganisms to generate genipin (4). Studies have proved that genipin also significantly reduces inflammation, lipid peroxidation and angiogenesis, with low cytotoxicity, sound biocompatibility and high anti-degradation ability (5,6). Gardenia jasminoides Ellis has a low genipin content, which only accounts for 0.005-0.01%, and mainly exists in the form of its precursor-geniposide, accounting for 3-5%. At present, geniposide is extracted with organic solvents, and 100 g gardenia fruit provide ~4 g geniposide. Therefore, it is of great significance to ferment Gardenia by microorganisms to produce genipin (7). In addition, the use of microorganisms and geniposide may achieve a better control of the concentration of active constituents, which may enhance the pharmacological effect. The transformation of geniposide contained in Gardenia jasminoides by fermentation with microorganisms is carried out by β-glucosidase produced by bacteria, which breaks chemical bonds in geniposide to produce genipin (8).In the present study, high-yield lactobacillus produced by β-glucosidase was used to react...

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Section: Discussionmentioning

confidence: 99%

Lactobacillus raises in vitro anticancer effect of geniposide in HSC‑3 human oral squamous cell carcinoma cells

Zhou

Wang

et al. 2017

Exp Ther Med

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“…25 Cancer metastasis is the major reason for high mortality of to suppress anti-apoptotic impact. 30 Experiment results indicated that knockdown of PANDAR inhibited the levels of Bcl-2 and reinforced the levels of Bax. In other hand, previous studies suggested that epithelial mesenchymal transition (EMT) was one of important mechanism in cell migration and invasion.…”

Section: Colorectal Cancermentioning

confidence: 99%

Long non‐coding PANDAR as a novel biomarker in human cancer: A systematic review

Zou

Zhong

et al. 2017

Cell Proliferation

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Objectives: Long non-coding RNAs (lncRNAs) are characterized as a group of RNAs that more than 200 nucleotides in length and have no protein-coding function. More and more evidences provided that lncRNAs serve as key molecules in the development of cancer. Deregulation of lncRNAs functions as either oncogenes or tumour suppressor genes in various diseases. Recently, increasing studies about PANDAR in cancer progression were reported. In our review, we will focus on the current research on the character of PANDAR include the clinical management, tumour progression and molecular mechanisms in human cancers. Materials and methods:We summarize and analyze current studies concerning the biological functions and mechanisms of lncRNA PANDA in tumour development. The related studies were obtained through a systematic search of Pubmed.Results: PANDAR was a well-characterized oncogenic lncRNA and widely overexpressed in many tumours. PANDAR is upregulated in many types of cancer, including colorectal cancer, lung cancer, renal cell carcinoma, cholangiocarcinoma, osteosarcoma, thyroid cancer and other cancers. Upregulation of PANDAR was significantly associated with advanced tumour weights, TNM stage and overall survival. Furthermore, repressed of PANDAR would restrain proliferation, migration and invasion. Conclusion:PANDAR may act as a powerful tumour biomarker for cancer diagnosis and treatment.

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“…Of note, literally all known BH3-only proteins can be rendered to become direct activators at least in vitro, depending on experimental conditions (Du et al 2011;Chen et al 2015). Hence, it is even more surprising that this autoactivation also happens in the absence of any known BH3-only protein ever reported to be involved in mitochondrial apoptosis or autophagy (O'Neill et al 2016). While these studies do not completely exclude an accelerating or modulatory role of direct interaction of some BH3-only proteins with BAX or BAK in a given cellular-or stimulus-dependent context, it challenges the universal validity of the "direct activation/embedded together" models.…”

mentioning

confidence: 99%

Interrogating the relevance of mitochondrial apoptosis for vertebrate development and postnatal tissue homeostasis

Tuzlak

Kaufmann

2016

Genes Dev.

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“Programmed cell death or ‘apoptosis’ is critical for organogenesis during embryonic development and tissue homeostasis in the adult. Its deregulation can contribute to a broad range of human pathologies, including neurodegeneration, cancer, or autoimmunity…” These or similar phrases have become generic opening statements in many reviews and textbooks describing the physiological relevance of apoptotic cell death. However, while the role in disease has been documented beyond doubt, facilitating innovative drug discovery, we wonder whether the former is really true. What goes wrong in vertebrate development or in adult tissue when the main route to apoptotic cell death, controlled by the BCL2 family, is impaired? Such scenarios have been mimicked by deletion of one or more prodeath genes within the BCL2 family, and gene targeting studies in mice exploring the consequences have been manifold. Many of these studies were geared toward understanding the role of BCL2 family proteins and mitochondrial apoptosis in disease, whereas fewer focused in detail on their role during normal development or tissue homeostasis, perhaps also due to an irritating lack of phenotype. Looking at these studies, the relevance of classical programmed cell death by apoptosis for development appears rather limited. Together, these many studies suggest either highly selective and context-dependent contributions of mitochondrial apoptosis or significant redundancy with alternative cell death mechanisms, as summarized and discussed here.

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Inactivation of prosurvival Bcl-2 proteins activates Bax/Bak through the outer mitochondrial membrane

Cited by 269 publications

References 63 publications

Lactobacillus raises in vitro anticancer effect of geniposide in HSC‑3 human oral squamous cell carcinoma cells

Lactobacillus raises in vitro anticancer effect of geniposide in HSC‑3 human oral squamous cell carcinoma cells

Long non‐coding PANDAR as a novel biomarker in human cancer: A systematic review

Interrogating the relevance of mitochondrial apoptosis for vertebrate development and postnatal tissue homeostasis

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