Abstract
Context Mechanical stresses, including compressive stress, arise during cancer progression. The rapid tumor growth and massive extra-cellular matrix remodeling of breast and pancreatic cancers explain the high intensity of compressive constraint in those pathologies. However, the transduction of compressive constraint into biochemical signals in cancer cells and the sensitivity of compressed cancer cells to therapies that target those signals remains poorly known.
Results We tested the effect of constant and high intensity 2D compression in four cancer cell lines where pharmacological and genetic PI3K inactivation alone decreased cell confluency. PI3K inhibition associated or not with compression accentuated cell confluency decrease and induced cell death, showing the importance of PI3K for cell survival under compression. Mechanistically, unbiased analysis identified that compression induced overexpression of PI3K isoforms and PI3K activation. Transcriptional effects of PI3K inhibition and compression converge to control mRNA and protein levels of an autophagy regulator GABARAP. PI3K inhibition and compression blocked autophagy, as assessed by accumulation of p62/SQSTM1 autophagosome cargo and decreased LC3B-II-mediated autophagy flux.
Conclusion This study provides evidence for the role of PI3K in compression mechanotransduction. The balance between cell death and autophagy mediated by GABARAP level may sustain cell survival in compressive stress environment.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Additional results were added, as well as further validation with genetically engeneered cell lines (with a genetic knock-down of PI3Kalpha). Further mechanistic experiments were added: autophagy levels by WB and IF, apoptosis quantifications using cytometry.
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE133134