Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia

Abstract

(2016) Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia, Autophagy, 12:6, 1029-1046, DOI: 10.1080/15548627.2016 ABSTRACTAutophagy is an intracellular lysosomal degradation pathway where its primary function is to allow cells to survive under stressful conditions. Autophagy is, however, a double-edge sword that can either promote cell survival or cell death. In cancer, hypoxic regions contribute to poor prognosis due to the ability of cancer cells to adapt to hypoxia in part through autophagy. In contrast, autophagy could contribute to hypoxia induced cell death in cancer cells. In this study, we showed that autophagy increased during hypoxia. At 4 h of hypoxia, autophagy promoted cell survival whereas, after 48 h of hypoxia, autophagy increased cell death. Furthermore, we found that the tyrosine phosphorylation of EGFR (epidermal growth factor receptor) decreased after 16 h in hypoxia. Furthermore, EGFR binding to BECN1 in hypoxia was significantly higher at 4 h compared to 72 h. Knocking down or inhibiting EGFR resulted in an increase in autophagy contributing to increased cell death under hypoxia. In contrast, when EGFR was reactivated by the addition of EGF, the level of autophagy was reduced which led to decreased cell death. Hypoxia led to autophagic degradation of the lipid raft protein CAV1 (caveolin 1) that is known to bind and activate EGFR in a ligand-independent manner during hypoxia. By knocking down CAV1, the amount of EGFR phosphorylation was decreased in hypoxia and amount of autophagy and cell death increased. This indicates that the activation of EGFR plays a critical role in the switch between cell survival and cell death induced by autophagy in hypoxia.

Metalloprotease-dependent activation of EGFR modulates CD44+/CD24− populations in triple negative breast cancer cells through the MEK/ERK pathway

“…The universally positive role of autophagy in CSC maintenance is, however, at odds with a report demonstrating that autophagy deficiency stabilizes the transcription factor TWIST1, promotes EMT in vitro , and tumor growth and metastasis using a A431 squamous cell carcinoma xenograft mouse model [60, 61]. Most importantly, in several cancer cell types, including breast cancer, EGFR activation suppresses autophagy [13, 20, 21]. Thus, EGFR inhibition should lead to an increase, rather than a decrease, in autophagy [22, 23], and the role of autophagy in EGFR-mediated regulation of breast CSCs needs further clarification.…”

Long non-coding RNAs act as regulators of cell autophagy in diseases

“…However, in the development of human diseases, autophagy has been shown to be a double-edged sword. In some cases, autophagy is a cytoprotective mechanism, but in others, autophagy is a pro-death response to stresses, especially chemotherapy at the cellular and organic levels (8,9). Many autophagy-related genes (Atgs) have been implicated in controlling these complicated behaviors during autophagy, and approximately half of them are evolutionarily conserved from yeast to human (10).…”

An inverted Caveolin-1 topology defines a novel exosome secreted from prostate cancer cells

“…Autophagy has been previously implicated in the release of proteins through atypical pathways [47][48][49][50][51] and several studies have linked degradation of Cav1 to autophagy [52][53][54][55] . Our EM studies demonstrated abundant small vesicles positive for Cav1 in the cytoplasm of expressing cells.…”