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

Abstract

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.

Cancer Microenvironment and Endoplasmic Reticulum Stress Response

“…Tumor cells adapt to low glucose levels by switching to a high rate of aerobic glycolysis, which is known as the Warburg effect [ 93 , 94 ]. The consequent lactic acid production reduces the pH, and low pH is an important feature of the tumor microenvironment, promoting tumor survival and progression also via UPR by regulating several BCL-2 family members and CHOP [ 95 ].…”

Gene expression profile analysis of SUDHL6 cells with siRNA‐mediated BCL11A downregulation

“…The tumor-suppressive function of c-JUN is probably related to its pro-apoptotic activity (Son et al, 2009;Ryder et al, 2013). We noted expression of JUN was upregulated in BCL11A siRNA treated SUDHL6 cells.…”

“…The SOS1 component of classic MAPK signaling pathway was also downregulated, it being critical for P38 activation (Jun et al, 2013). The tumor-suppressive function of c-JUN is probably related to its pro-apoptotic activity (Son et al, 2009;Ryder et al, 2013). We noted expression of JUN was upregulated in BCL11A siRNA treated SUDHL6 cells.…”

Xiao-Ai-Ping, a TCM Injection, Enhances the Antigrowth Effects of Cisplatin on Lewis Lung Cancer Cells through Promoting the Infiltration and Function of CD8+T Lymphocytes

“…Proliferating cell nuclear antigen (PCNA) and phosphorylation of protein kinase B (Akt) are markers for tumor growth [32, 33]. DNA damage-inducible transcript 3, also known as C/EBP homologous protein (CHOP), is a key marker for tumor apoptosis [34, 35]. Compared with sole drug treatment, 1 mg/kg cisplatin combined with 20 g crude/kg Xiao-Ai-Ping significantly decreased the protein levels of PCNA (Figure 3(a)) and phosphorylated Akt (Thr 308) (Figure 3(b)) in LLC xenografts.…”