Pivotal Role of the Cell Death Factor BNIP3 in Ceramide-Induced Autophagic Cell Death in Malignant Glioma Cells

Daido, Shigeru; Kanzawa, Takao; Yamamoto, Akira; Takeuchi, Hayato; Kondo, Yasuko; Kondo, Seiji

doi:10.1158/0008-5472.can-03-3084

Cited by 391 publications

(342 citation statements)

References 45 publications

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“…The diverse range of cellular responses elicited by an intracellular accumulation in the sphingolipid second messenger ceramide [3][4][5]7,8 are underscored by tissue specificity. It has been reported that treatment strategies utilized in the treatment of RMS (IR and chemotherapy) 27 require the generation of ceramide for apoptosis to be initialized as part of their tumoricidal action.…”

Section: Discussionmentioning

confidence: 99%

“…2 While the majority of studies evaluating the effects of an elevation in cellular ceramide have focused on its ability to induce apoptosis, 1,3 several other studies have also described ceramide to be necessary for the induction of senescence, 4 cell-cell interactions, 5 death receptor clustering 6 and autophagy. 7 Collectively these studies emphasize that the cellular response to elevations in ceramide are tissuespecific and that ceramide is capable of modulating several biochemical pathways. In this regard, data describing ceramide to mediate G 0 /G 1 arrest, 3,4,8 and to accumulate following the release of cells from G 2 /M arrest, 9 also implicate a role for ceramide in cell cycle progression and regulation.…”

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confidence: 99%

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Ceramide-induced G2 arrest in rhabdomyosarcoma (RMS) cells requires p21Cip1/Waf1 induction and is prevented by MDM2 overexpression

et al. 2007

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The sphingoplipid ceramide is responsible for a diverse range of biochemical and cellular responses including a putative role in modulating cell cycle progression. Herein, we describe that an accumulation of ceramide, achieved through the exogenous application of C 6 -ceramide or exposure to sphingomyelinase, induces a G 2 arrest in Rhabdomyosarcoma (RMS) cell lines. Utilizing the RMS cell line RD, we show that this G 2 arrest required the rapid induction of p21 Cip1/Waf1 independent of DNA damage. This was followed at later time points (48 h) by the commitment to apoptosis. Apoptosis was prevented by Bcl-2 overexpression, but permitted the maintenance of elevated p21 Cip1/Waf1 protein expression and the stabilization of the G 2 arrest response. Inhibition of p21 Cip1/Waf1 protein synthesis with cyclohexamide (CHX) or silencing of p21 Cip1/Waf1 with siRNA, prevented ceramide-mediated G 2 arrest and the late induction of apoptosis. Further, adopting the recent discovery that murine double minute 2 (MDM2) controls p21 Cip1/Waf1 expression by presenting this CDK inhibitor to the proteasome for degradation, RD cells overexpressing MDM2 abrogated ceramide-mediated p21 Cip1/Waf1 induction, G 2 arrest and the late ensuing apoptosis. Collectively, these data further support the notion that ceramide accumulation can modulate cell cycle progression. Additionally, these observations highlight MDM2 expression and proteasomal activity as key determinants of the cellular response to ceramide accumulation.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Ceramide-induced G2 arrest in rhabdomyosarcoma (RMS) cells requires p21Cip1/Waf1 induction and is prevented by MDM2 overexpression

et al. 2007

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“…15 Treating cells with toxins that induce cell death, such as arsenic trioxide and cyanide, or with cellular products ceramide and amyloid-b also induce BNIP3 expression mediated by HIF-1 activation. 16,[12][13][14] In addition, transcription factor E2F-1 binds to the bnip3 promoter and induces its expression in rat ventricular myocytes. 17 Therefore, it is becoming apparent that many cellular stresses such as hypoxia or toxins lead to increased BNIP3 expression.…”

Section: How Is Bnip3 Expression Regulated?mentioning

confidence: 99%

“…29 Overexpression of BNIP3 can also induce autophagic cell death, measured by observation of autophagic vacuoles by EM, localization and processing of light chain 3 (LC3), which is a protein that is incorporated in autophagic membranes upon formation. 16,12,18,34 BNIP3-induced cell death is blocked by an inhibitor of autophagy (3-methyladenine), but not by an inhibitor of apoptosis (N-CBZ-Val-Aal-Asp(O-Me) fluoromethyl ketone). Knockdown of BNIP3 blocked hypoxia-induced autophagy and cell death, but did not block localization of LC3 with autophagosomes, therefore suggesting that BNIP3 is involved in autophagosome-lysosome fusion.…”

Section: Bnip3mentioning

confidence: 99%

The role of Bcl-2 family member BNIP3 in cell death and disease: NIPping at the heels of cell death

2009

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Bcl-2 nineteen-kilodalton interacting protein (BNIP3) is a BH-3-only Bcl-2 family member whose expression levels increase during stress such as hypoxia through hypoxia-inducing factor-1-dependent or -independent mechanisms. When BNIP3 expression is induced, it localizes to the mitochondria and triggers a loss of membrane potential, and an increase in the reactive oxygen species production, which often leads to cell death. Cells under normal growth conditions suppress BNIP3 expression through transcriptional repression. There is considerable debate in the literature regarding what type of cell death is induced by BNIP3. It has been observed that BNIP3 could induce necrosis, autophagy and/or apoptosis. In contrast, other studies indicate that BNIP3 could promote cell survival. Besides its cell death regulation, BNIP3 plays a key role in the pathogenicity of many diseases. In cardiac infarction, loss of BNIP3 expression has been shown to reduce the number of damaged cardiomyocytes after ischemia and reperfusion. BNIP3 expression also plays an important role in the deregulation of cell death in many cancers. In this review, we will discuss the different and often contradictory mechanisms of BNIP3 regulation of cell death and the role that BNIP3 may play in diseases. Bcl-2 nineteen-kilodalton interacting protein (BNIP3) belongs to the Bcl-2 homology domain (BH3)-only Bcl-2 family members because it only contains a putative BH3 domain. 1 The other major domains found in BNIP3 are the PEST domain that targets BNIP3 for degradation, a conserved domain that is conserved from Caenorhabditis elegans to humans and a transmembrane (TM) domain, which targets BNIP3 to the mitochondria (Figure 1). 2 BH3-only containing proteins act as rheostats regulating apoptosis through their BH3 domain by binding to antiapoptotic Bcl-2 family members. However, BNIP3 differs from these members, as its BH3 domain fails to interact with antiapoptotic Bcl-2 family members. 3 Furthermore, deletions of the BH3 domain fail to affect the ability of BNIP3 to induce cell death. 4 Unlike other BH3-only family members, BNIP3 interacts with Bcl-2 and Bcl-X L through its TM domain and N terminus (amino acids 1-49). 3 Deletion of the TM domain blocks the ability of BNIP3 to induce cell death. 4 BNIP3 migrates at 30 and 60 kDa, indicating that BNIP3 is a protein that forms homodimers. This homodimerization is primarily through the TM domain of BNIP3. The unique structure of the TM domain suggests that BNIP3 dimers could act as proton channels in the outer mitochondrial membrane increasing ion conductance. 5 Serine 172 and histidine (His) 173 are residues that are present in the dimerization interface of BNIP3. These residues interact by hydrogen bonds and are essential for dimer formation. 6 Furthermore, mutation of the His 173 to alanine completely abrogated the ability of BNIP3 to induce cell death. 7 Bcl-2 and Bcl-X L can compete for binding to the TM domain, which blocks BNIP3 homodimerization and abrogates the ability of BNIP3 to induce cell death (Fi...

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“…For verification, cell death was analyzed by measuring the permeability of the cell membrane to AO staining as described in Materials and methods. The formation of acidic vesicular organelles (AVOs), is one of the characteristic features of cells which passes through the process of autophagy after exposure of different autophagy inducer agents (42,43). Autophagic vacuoles (AVOs) or autophagosomes are formed as a result of sequestering the parts of the cytoplasm or entire organelles respectively during the process of autophagy (31).…”

Section: Resultsmentioning

confidence: 99%

Cytotoxic effect of evodiamine in SGC-7901 human gastric adenocarcinoma cells via simultaneous induction of apoptosis and autophagy

2012

Oncol Rep

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Abstract. Evodiamine, an alkaloid isolated from Evodia rutaecarpa, possesses potent anticancer activity. Although many reports have elucidated the cytotoxic effects of evodiamine in a variety of cancer cells, little is known about the mechanism of evodiamine-induced cytotoxic activity in gastric cancer cells. To date, no report has addressed the synchronized role of autophagy and apoptosis in evodiamineinduced cytotoxic activity. This study was conducted to investigate the synchronized role of autophagy and apoptosis in evodiamine-induced cytotoxic activity on SGC-7901 human gastric adenocarcinoma cells and further to elucidate the underlying molecular mechanisms. The MTT assay was used to examine the cytotoxicity of evodiamine against SGC-7901 gastric adenocarcinoma cells. The effects of evodiamine on the cell cycle and apoptosis were measured by flow cytometry and cellular morphology was observed under a phase contrast microscope. Acridine orange (AO) staining was used to detect autophagy. The expression levels of Bcl-2 and Bax were detected by Western blotting. The expression level of Beclin-1 in SGC-7901 cells was monitored by reverse transcription-polymerase chain reaction (RT-PCR). Here, we found that evodiamine significantly inhibited the proliferation of SGC-7901 cells and induced G2/M phase cell cycle arrest. Furthermore, both autophagy and apoptosis were activated during the evodiamine-induced death of SGC-7901 cells. Evodiamine-induced autophagy is partially involved in the death of SGC-7901 cells which was confirmed by using the autophagy inhibitor 3-methyladenine (3-MA). Additionally, Beclin-1 is involved in evodiamine-induced autophagy and the pro-apoptotic mechanisms of evodiamine may be associated with down-regulation of Bcl-2 and up-regulation of Bax expression. The inhibitory effects on SGC-7901 cells were associated with apoptosis, autophagy and cell cycle arrest at the G2/M phase in a dose-dependent manner. These results suggest that evodiamine is an effective natural compound for the treatment of gastric cancer and may represent a candidate for in vivo studies of monotherapies or combined antitumor therapies.

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Pivotal Role of the Cell Death Factor BNIP3 in Ceramide-Induced Autophagic Cell Death in Malignant Glioma Cells

Cited by 391 publications

References 45 publications

Ceramide-induced G2 arrest in rhabdomyosarcoma (RMS) cells requires p21Cip1/Waf1 induction and is prevented by MDM2 overexpression

Ceramide-induced G2 arrest in rhabdomyosarcoma (RMS) cells requires p21Cip1/Waf1 induction and is prevented by MDM2 overexpression

The role of Bcl-2 family member BNIP3 in cell death and disease: NIPping at the heels of cell death

Cytotoxic effect of evodiamine in SGC-7901 human gastric adenocarcinoma cells via simultaneous induction of apoptosis and autophagy

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