Apr 21, 2020

AMPK-Fyn signaling promotes Notch1 stability to potentiate hypoxia-induced breast cancer stemness and drug resistance

BioRxiv : the Preprint Server for Biology
Mohini LahiryAnnapoorni Rangarajan

Abstract

Hypoxia is a hall mark of solid tumor microenvironment and contributes to tumor progression and therapy failure. The developmentally important Notch pathway is implicated in cellular response of cancer cells to hypoxia. Yet, the mechanisms that potentiate Notch signaling under hypoxia are not fully understood. Hypoxia is also a stimulus for AMP-activated protein kinase (AMPK), a major cellular energy sensor. In this study, we investigated if AMPK interacts with the Notch pathway and influences the hypoxia-response of breast cancer cells. Activating AMPK with pharmacological agent or genetic approaches led to an increase in the levels of cleaved Notch1 and elevated Notch signaling in invasive breast cancer cell lines. In contrast, inhibition or depletion of AMPK reduced the amount of cleaved Notch1. Significantly, we show that the hypoxia-induced increase in cleaved Notch1 levels requires AMPK activation. Probing into the mechanism, we demonstrate that AMPK activation impairs the interaction between cleaved Notch1 and its ubiquitin ligase, Itch/AIP4 through the tyrosine kinase Fyn. Under hypoxia, the AMPK-Fyn axis promotes inhibitory phosphorylation of Itch which abrogates its interaction with substrates, thus stabilizing cleave...Continue Reading

  • References
  • Citations

References

  • We're still populating references for this paper, please check back later.
  • References
  • Citations

Citations

  • This paper may not have been cited yet.

Mentioned in this Paper

Biochemical Pathway
Notch
Cleaved
Regulation of Biological Process
Ubiquitin
Genetic Analysis
PRKAA2 gene
Receptor Down-Regulation
Protein Phosphorylation
Cancer Progression

About this Paper

Related Feeds

Breast Cancer: Chemo-Resistance

Some cancers are difficult to treat and aggressive including the "triple-negative" breast cancer. This type of cancer is chemoresistant even before chemotherapy begins. Here are the latest discoveries chemo-resistance in breast cancer.

BioRxiv & MedRxiv Preprints

BioRxiv and MedRxiv are the preprint servers for biology and health sciences respectively, operated by Cold Spring Harbor Laboratory. Here are the latest preprint articles (which are not peer-reviewed) from BioRxiv and MedRxiv.