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ATF4 contributes to autophagy and survival in sunitinib treated brain tumor initiating cells (BTICs).

ABSTRACT: Receptor tyrosine kinase (RTK) pathways are known to play an important role in tumor cell proliferation of glioblastoma (GBM). Cellular determinants of RTK-inhibitor sensitivity are important to optimize and tailor treatment strategies. The stress response gene activating transcription factor 4 (ATF4) is involved in homeostasis and cellular protection. However, little is known about its function in GBM. We found that the ATF4/p-eIF2? pathway is activated in response to Sunitinib in primary tumor initiating progenitor cell cultures (BTICs). Furthermore, lysosome entrapment of RTK-inhibitors (RTK-Is) leads to accumulation of autophagosomes. In case of Sunitinib treated cells, autophagy is additionally increased by ATF4 mediated upregulation of autophagy genes. Inhibition of ATF4 by small interfering RNA (siRNA) reduced autophagy and cell proliferation after Sunitinib treatment in a subset of BTIC cultures. Overall, this study suggests a pro-survival role of the ATF4/p-eIF2? pathway in a cell type and treatment specific manner.

SUBMITTER: Moeckel S

PROVIDER: S-EPMC6349458 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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ATF4 contributes to autophagy and survival in sunitinib treated brain tumor initiating cells (BTICs).

Moeckel Sylvia S LaFrance Kelly K Wetsch Julia J Seliger Corinna C Riemenschneider Markus J MJ Proescholdt Martin M Hau Peter P Vollmann-Zwerenz Arabel A

Oncotarget 20190108 3

Receptor tyrosine kinase (RTK) pathways are known to play an important role in tumor cell proliferation of glioblastoma (GBM). Cellular determinants of RTK-inhibitor sensitivity are important to optimize and tailor treatment strategies. The stress response gene activating transcription factor 4 (ATF4) is involved in homeostasis and cellular protection. However, little is known about its function in GBM. We found that the ATF4/p-eIF2α pathway is activated in response to Sunitinib in primary tumor ...[more]

PMID: 30719230

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Project description:As glutamine plays a central role in cancer metabolism, inhibition of glutaminolysis has become an ideal anticancer therapeutic target. However, glutaminolysis inhibition leads to activation of autophagy, which compromises its antitumor effect. Hence, we investigated the mechanism underlying glutaminolysis inhibition-induced pro-survival autophagy. Methods: High-throughput sequencing was performed on colorectal cancer (CRC) cells before and after glutaminolysis inhibition to identify differentially expressed genes. Activating transcription factor 4 (ATF4) pathway enrichment in glutaminolysis inhibited cells was identified through gene set enrichment analysis. ATF4 expression was assessed by quantitative real-time PCR (qRT-PCR) and western blotting. The function of ATF4 on mechanistic target of rapamycin (mTOR) regulation was assessed by western blotting. Luciferase reporter assays and chromatin immunoprecipitation were used to confirm the regulation of DNA damage inducible transcript 4 (DDIT4) by ATF4. mRNA half-life assays, RNA immunoprecipitation, qRT-PCR and western blotting were performed to determine the relationship between FTO alpha-ketoglutarate dependent dioxygenase (FTO), YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), and ATF4. ATF4 regulation of pro-survival autophagy was measured by tandem monomeric red fluorescent protein-green fluorescent protein fluorescence microscopy. Finally, the synergistic effect of autophagy and glutaminolysis inhibition was analyzed in an azoxymethane/dextran sodium sulfate mouse model. Results: The ATF4 pathway was activated in CRC cells upon glutaminolysis inhibition. Functionally, ATF4 transcriptionally upregulated DDIT4 to suppress mTOR, which induced pro-survival autophagy during glutaminolysis inhibition. Interestingly, glutaminolysis inhibition promoted ATF4 mRNA expression by abrogating N6-methyladenosine (m6A) modification and YTHDF2-mediated RNA decay. Finally, inhibition of ATF4-induced autophagy enhanced the antitumor efficacy of glutaminolysis inhibition. Conclusion: Glutaminolysis inhibition upregulated ATF4 expression in an m6A-dependent manner to activate pro-survival autophagy through transcriptional activation of the mTOR inhibitor DDIT4. Targeting ATF4-induced autophagy is a new strategy to synergize glutaminolysis-targeting therapies for cancer treatment.

Dataset Information

ATF4 contributes to autophagy and survival in sunitinib treated brain tumor initiating cells (BTICs).

Publications

ATF4 contributes to autophagy and survival in sunitinib treated brain tumor initiating cells (BTICs).

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