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PACS-2 mediates the ATM and NF-?B-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage.

ABSTRACT: Nuclear factor kappa B (NF-?B) promotes cell survival in response to genotoxic stress by inducing the expression of anti-apoptotic proteins including Bcl-xL, which protects mitochondria from stress-induced mitochondrial outer membrane permeabilization (MOMP). Here we show that the multifunctional sorting protein Pacs-2 (phosphofurin acidic cluster sorting protein-2) is required for Bcl-xL induction following DNA damage in primary mouse thymocytes. Consequently, in response to DNA damage, Pacs-2(-/-) thymocytes exhibit a blunted induction of Bcl-xL, increased MOMP and accelerated apoptosis. Biochemical studies show that cytoplasmic PACS-2 promotes this DNA damage-induced anti-apoptotic pathway by interacting with ataxia telangiectasia mutated (ATM) to drive NF-?B activation and induction of Bcl-xL. However, Pacs-2 was not required for tumor necrosis factor-?-induced NF-?B activation, suggesting a role for PACS-2 selectively in NF-?B activation in response to DNA damage. These findings identify PACS-2 as an in vivo mediator of the ATM and NF-?B-dependent induction of Bcl-xL that promotes cell survival in response to DNA damage.

SUBMITTER: Barroso-Gonzalez J

PROVIDER: S-EPMC5072422 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage.

Barroso-González J J Auclair S S Luan S S Thomas L L Atkins K M KM Aslan J E JE Thomas L L LL Zhao J J Zhao Y Y Thomas G G

Cell death and differentiation 20160304 9

Nuclear factor kappa B (NF-κB) promotes cell survival in response to genotoxic stress by inducing the expression of anti-apoptotic proteins including Bcl-xL, which protects mitochondria from stress-induced mitochondrial outer membrane permeabilization (MOMP). Here we show that the multifunctional sorting protein Pacs-2 (phosphofurin acidic cluster sorting protein-2) is required for Bcl-xL induction following DNA damage in primary mouse thymocytes. Consequently, in response to DNA damage, Pacs-2( ...[more]

PMID: 26943323

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Project description:BackgroundNew therapeutic targets are needed to improve the outcomes for gastric cancer (GC) patients with advanced disease. Evasion of programmed cell death (apoptosis) is a hallmark of cancer cells and direct induction of apoptosis by targeting the pro-survival BCL2 family proteins represents a promising therapeutic strategy for cancer treatment. Therefore, understanding the molecular mechanisms underpinning cancer cell survival could provide a molecular basis for potential therapeutic interventions.MethodHere we explored the role of BCL2L1 and the encoded anti-apoptotic BCL-XL in GC. Using Droplet Digital PCR (ddPCR) technology to investigate the DNA amplification of BCL2L1 in GC samples and GC cell lines, the sensitivity of GC cell lines to selective BCL-XL inhibitors A1155463 and A1331852, pan-inhibitor ABT-263, and VHL-based PROTAC-BCL-XL was analyzed using (CellTiter-Glo) CTG assay in vitro. Western Blot (WB) was used to detect the protein expression of BCL2 family members in GC cell lines and the manner in which PROTAC-BCL-XL kills GC cells. Co-immunoprecipitation (Co-IP) was used to investigate the mechanism of A1331852 and ABT-263 kills GC cell lines. DDPCR, WB, and real-time PCR (RTPCR) were used to investigate the correlation between DNA, RNA, protein levels, and drug activity.ResultsThe functional assay showed that a subset of GC cell lines relies on BCL-XL for survival. In gastric cancer cell lines, BCL-XL inhibitors A1155463 and A1331852 are more sensitive than the pan BCL2 family inhibitor ABT-263, indicating that ABT-263 is not an optimal inhibitor of BCL-XL. VHL-based PROTAC-BCL-XL DT2216 appears to be active in GC cells. DT2216 induces apoptosis of gastric cancer cells in a time- and dose-dependent manner through the proteasome pathway. Statistical analysis showed that the BCL-XL protein level predicts the response of GC cells to BCL-XL targeting therapy and BCL2L1 gene CNVs do not reliably predict BCL-XL expression.ConclusionWe identified BCL-XL as a promising therapeutic target in a subset of GC cases with high levels of BCL-XL protein expression. Functionally, we demonstrated that both selective BCL-XL inhibitors and VHL-based PROTAC BCL-XL can potently kill GC cells that are reliant on BCL-XL for survival. However, we found that BCL2L1 copy number variations (CNVs) cannot reliably predict BCL-XL expression, but the BCL-XL protein level serves as a useful biomarker for predicting the sensitivity of GC cells to BCL-XL-targeting compounds. Taken together, our study pinpointed BCL-XL as potential druggable target for specific subsets of GC.

Dataset Information

PACS-2 mediates the ATM and NF-?B-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage.

Publications

PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage.

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