Acidosis Promotes Bcl-2 Family-mediated Evasion of Apoptosis

Ryder, Chris; McColl, Karen; Zhong, Fei; Distelhorst, Clark W.

doi:10.1074/jbc.m112.384685

Cited by 59 publications

(42 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Maintenance and experimental conditions for wild type and Bcl-2-expressing WEHI7.2 cells were previously described [11]. Initial cell density of 3–6 × 10 5 cells/mL was used for all experiments.…”

Section: Methodsmentioning

confidence: 99%

“…Protocol was described previously [11]. Antibodies used include: anti-PUMA, anti-Bim, anti-CHOP, anti-c-Jun, anti-cleaved caspase-3, and anti-PARP from Cell Signaling, and anti-Actin from Sigma.…”

Section: Methodsmentioning

confidence: 99%

“…RNA isolation and RT-PCR were performed as described previously [11]. All assays were created from Roche universal probe library.…”

Section: Methodsmentioning

confidence: 99%

“…We recently reported that acidosis inhibits apoptosis of starved or stressed lymphoma cells through regulation of multiple members of the Bcl-2 family [11]. This group consists of over 20 proteins that share homology in at least one of four distinct Bcl-2 homology (BH) domains [12].…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Acidosis blocks CCAAT/enhancer-binding protein homologous protein (CHOP)- and c-Jun-mediated induction of p53-upregulated mediator of apoptosis (PUMA) during amino acid starvation

Ryder

McColl

Distelhorst

2013

Biochemical and Biophysical Research Communications

Self Cite

View full text Add to dashboard Cite

Cancer cells must avoid succumbing to a variety of noxious conditions within their surroundings. Acidosis is one such prominent feature of the tumor microenvironment that surprisingly promotes tumor survival and progression. We recently reported that acidosis prevents apoptosis of starved or stressed lymphoma cells through regulation of several Bcl-2 family members (Ryder et al., JBC, 2012). Mechanistic studies in that work focused on the acid-mediated upregulation of anti-apoptotic Bcl-2 and Bcl-xL, while additionally showing inhibition of glutamine starvation-induced expression of pro-apoptotic PUMA by acidosis. Herein we report that amino acid (AA) starvation elevates PUMA, an effect that is blocked by extracellular acidity. Knockdown studies confirm that PUMA induction during AA starvation requires expression of both CHOP and c-Jun. Interestingly, acidosis strongly attenuates AA starvation-mediated c-Jun expression, which correlates with PUMA repression. As c-Jun exerts a tumor suppressive function in this and other contexts, its inhibition by acidosis has broader implications for survival of cancer cells in the acidic tumor milieu.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…RNA isolation and RT-PCR were performed as described previously [11]. All assays were created from Roche universal probe library.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Acidosis blocks CCAAT/enhancer-binding protein homologous protein (CHOP)- and c-Jun-mediated induction of p53-upregulated mediator of apoptosis (PUMA) during amino acid starvation

Ryder

McColl

Distelhorst

2013

Biochemical and Biophysical Research Communications

Self Cite

View full text Add to dashboard Cite

show abstract

“…16, 17, 18 Moreover, we have previously reported that local acidosis moderately delays the rate of neutrophil apoptosis, 14 and a similar anti-apoptotic effect was reported for endothelial and cancer cells. 19, 20 …”

mentioning

confidence: 99%

Fever-range hyperthermia improves the anti-apoptotic effect induced by low pH on human neutrophils promoting a proangiogenic profile

et al. 2016

View full text Add to dashboard Cite

Neutrophils have the shortest lifespan among leukocytes and usually die via apoptosis, limiting their deleterious potential. However, this tightly regulated cell death program can be modulated by pathogen-associated molecular patterns (PAMPs), danger-associated molecular pattern (DAMPs), and inflammatory cytokines. We have previously reported that low pH, a hallmark of inflammatory processes and solid tumors, moderately delays neutrophil apoptosis. Here we show that fever-range hyperthermia accelerates the rate of neutrophil apoptosis at neutral pH but markedly increases neutrophil survival induced by low pH. Interestingly, an opposite effect was observed in lymphocytes; hyperthermia plus low pH prevents lymphocyte activation and promotes the death of lymphocytes and lymphoid cell lines. Analysis of the mechanisms through which hyperthermia plus low pH increased neutrophil survival revealed that hyperthermia further decreases cytosolic pH induced by extracellular acidosis. The fact that two Na+/H+ exchanger inhibitors, 5-(N-ethyl-N-isopropyl) amiloride (EIPA) and amiloride, reproduced the effects induced by hyperthermia suggested that it prolongs neutrophil survival by inhibiting the Na+/H+ antiporter. The neutrophil anti-apoptotic effect induced by PAMPs, DAMPs, and inflammatory cytokines usually leads to the preservation of the major neutrophil effector functions such as phagocytosis and reactive oxygen species (ROS) production. In contrast, our data revealed that the anti-apoptotic effect induced by low pH and hyperthermia induced a functional profile characterized by a low phagocytic activity, an impairment in ROS production and a high ability to suppress T-cell activation and to produce the angiogenic factors VEGF, IL-8, and the matrix metallopeptidase 9 (MMP-9). These results suggest that acting together fever and local acidosis might drive the differentiation of neutrophils into a profile able to promote both cancer progression and tissue repair during the late phase of inflammation, two processes that are strongly dependent on the local production of angiogenic factors by infiltrating immune cells.

show abstract

Inhibition of MCL‐1 by obatoclax sensitizes Sp2/0‐Ag14 hybridoma cells to glutamine deprivation‐induced apoptosis

Harnett

Abusneina

Clément

et al. 2015

Cell Biochemistry & Function

View full text Add to dashboard Cite

For several cancer cell types, the lack of an adequate supply of the amino acidl-glutamine (Gln) triggers apoptosis, a phenomenon termed Gln addiction. In this report, we examined the role of the anti-apoptotic proteins of the B-cell lymphoma 2 (BCL-2) protein family in the survival of Sp2/0-Ag14 (Sp2/0) mouse hybridoma cells, a cell line that undergoes apoptosis within minutes of Gln deprivation. Western blot analysis revealed that myeloid cell leukaemia 1 (MCL-1) was expressed at much higher levels than BCL-2, B-cell lymphoma extra-large and BCL-2-like protein 2 making it the prominent pro-survival BCL-2 family member in this hybridoma. Gln deprivation triggered a progressive decrease in MCL-1 protein levels, which coincided with the decrease in Sp2/0 cell survival. Moreover, Sp2/0 cells were much more sensitive to the broad Bcl-2 homology domain-3 (BH3) mimetic obatoclax (which targets MCL-1) than to the more selective drug ABT-737 (which does not target MCL-1). Finally, we show that obatoclax sensitizes Sp2/0 cells to apoptosis following Gln starvation. All together, the data presented here reveal that modulation of the pro-survival protein MCL-1 is an important step in the sequence of events leading to the initiation of apoptosis in Gln-starved Sp2/0 cells. Cancer cells require an adequate supply ofl-glutamine for their survival. Using a mouse hybridoma cell line that is exquisitely sensitive to glutamine starvation, we show that the levels of the pro-survival BCL-2 family protein MCL-1 decrease upon glutamine starvation in a manner that correlates with the loss of cell viability. Moreover, inhibiting MCL-1 with the drug obatoclax sensitizes hybridoma cells to glutamine starvation. Thus, in some cancer cells, glutamine starvation triggers the inactivation of pro-survival proteins. Our data suggest that the combined inhibition of glutamine biosynthesis pathways and BCL-2 proteins may prove effective against some cancers.

show abstract

Acidosis Promotes Bcl-2 Family-mediated Evasion of Apoptosis

Cited by 59 publications

References 70 publications

Acidosis blocks CCAAT/enhancer-binding protein homologous protein (CHOP)- and c-Jun-mediated induction of p53-upregulated mediator of apoptosis (PUMA) during amino acid starvation

Acidosis blocks CCAAT/enhancer-binding protein homologous protein (CHOP)- and c-Jun-mediated induction of p53-upregulated mediator of apoptosis (PUMA) during amino acid starvation

Fever-range hyperthermia improves the anti-apoptotic effect induced by low pH on human neutrophils promoting a proangiogenic profile

Inhibition of MCL‐1 by obatoclax sensitizes Sp2/0‐Ag14 hybridoma cells to glutamine deprivation‐induced apoptosis

Contact Info

Product

Resources

About