Robustness of the Autophagy Pathway to Somatic Copy Number Losses

Robustness of the Autophagy Pathway to Somatic Copy Number Losses

Autophagy allows cells to temporarily tolerate energy stress by replenishing critical metabolites through self-digestion, thereby attenuating the cytotoxic effects of anticancer drugs that target tumor metabolism. Autophagy defects could therefore mark a metabolically vulnerable cancer state and ope...

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Detaylı Bibliyografya
Asıl Yazarlar: Polo, Pierfrancesco, Gremke, Niklas, Stiewe, Thorsten, Wanzel, Michael
Materyal Türü: Makale
Dil:İngilizce
Baskı/Yayın Bilgisi: Philipps-Universität Marburg 2023
Konular:
aerobic glycolysis
cancer metabolism
somatic copy number alterations (SCNAs)
Medizin
metabolic cancer ther
copy number loss
haploinsufficiency
autophagy
Medical sciences Medicine
Online Erişim:PDF Tam Metin
Etiketler: Etiketle
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Diğer Bilgiler
Özet:Autophagy allows cells to temporarily tolerate energy stress by replenishing critical metabolites through self-digestion, thereby attenuating the cytotoxic effects of anticancer drugs that target tumor metabolism. Autophagy defects could therefore mark a metabolically vulnerable cancer state and open a therapeutic window. While mutations of autophagy genes (ATGs) are notably rare in cancer, haploinsufficiency network analyses across many cancers have shown that the autophagy pathway is frequently hit by somatic copy number losses of ATGs such as MAP1LC3B/ATG8F (LC3), BECN1/ATG6 (Beclin-1), and ATG10. Here, we used CRISPR/Cas9 technology to delete increasing numbers of copies of one or more of these ATGs in non-small cell lung cancer cells and examined the effects on sensitivity to compounds targeting aerobic glycolysis, a hallmark of cancer metabolism. Whereas the complete knockout of one ATG blocked autophagy and led to profound metabolic vulnerability, this was not the case for combinations of different nonhomozygous deletions. In cancer patients, the effect of ATG copy number loss was blunted at the protein level and did not lead to the accumulation of p62 as a sign of reduced autophagic flux. Thus, the autophagy pathway is shown to be markedly robust and resilient, even with the concomitant copy number loss of key autophagy genes.
Diğer Bilgileri:Gefördert durch den Open-Access-Publikationsfonds der UB Marburg.
Fiziksel Özellikler:15 Seiten
DOI:10.3390/cells11111762

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