Annexin A1 sustains tumor metabolism and cellular proliferation upon stable loss of HIF1A

Rohwer, N.; Bindel, F.; Grimm, C.; Lin, S.J.; Wappler, J.; Klinger, B.; Blüthgen, N.; Du Bois, I.; Schmeck, B.; Lehrach, H.; de Graauw, M.; Goncalves, E.; Saez-Rodriguez, J.; Tan, P.; Grabsch, H.I.; Prigione, A.; Kempa, S.; Cramer, T.

Annexin A1 sustains tumor metabolism and cellular proliferation upon stable loss of HIF1A

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Item Type:	Article
Title:	Annexin A1 sustains tumor metabolism and cellular proliferation upon stable loss of HIF1A
Creators Name:	Rohwer, N., Bindel, F., Grimm, C., Lin, S.J., Wappler, J., Klinger, B., Blüthgen, N., Du Bois, I., Schmeck, B., Lehrach, H., de Graauw, M., Goncalves, E., Saez-Rodriguez, J., Tan, P., Grabsch, H.I., Prigione, A., Kempa, S. and Cramer, T.
Abstract:	Despite the approval of numerous molecular targeted drugs, long-term antiproliferative efficacy is rarely achieved and therapy resistance remains a central obstacle of cancer care. Combined inhibition of multiple cancer-driving pathways promises to improve antiproliferative efficacy. HIF-1 is a driver of gastric cancer and considered to be an attractive target for therapy. We noted that gastric cancer cells are able to functionally compensate the stable loss of HIF-1{alpha}. Via transcriptomics we identified a group of upregulated genes in HIF-1{alpha}-deficient cells and hypothesized that these genes confer survival upon HIF-1{alpha} loss. Strikingly, simultaneous knock-down of HIF-1{alpha} and Annexin A1 (ANXA1), one of the identified genes, resulted in complete cessation of proliferation. Using stable isotope-resolved metabolomics, oxidative and reductive glutamine metabolism was found to be significantly impaired in HIF-1{alpha}/ANXA1-deficient cells, potentially explaining the proliferation defect. In summary, we present a conceptually novel application of stable gene inactivation enabling in-depth deconstruction of resistance mechanisms. In theory, this experimental approach is applicable to any cancer-driving gene or pathway and promises to identify various new targets for combination therapies.
Keywords:	Cancer Therapy, Annexin A1, Cancer Metabolism, HIF-1, Induced Essentiality, Animals, Mice
Source:	Oncotarget
ISSN:	1949-2553
Publisher:	Impact Journals
Volume:	7
Number:	6
Page Range:	6693-6710
Date:	29 December 2015
Official Publication:	https://doi.org/10.18632/oncotarget.6793
PubMed:	View item in PubMed

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