Induction of Endoplasmic Reticulum Stress by Sonoporation: Linkage to Mitochondria-Mediated Apoptosis Initiation
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The use of cavitational means to create transient membrane pores on living cells (i.e., sonoporation) may potentially induce a broad range of downstream bio-effects that disrupt the functioning of various organelles. Here we observed that on HL-60 leukemia cells, sonoporation may induce endoplasmic reticulum (ER) stress on a time-lapse basis and, in turn, signal the mitochondria to commit a cell toward apoptosis. Our observations were derived from invitro ultrasound exposure experiments performed on HL-60 cells in the presence of lipid-shelled microbubbles (1:1 cell-to-bubble ratio; 1-MHz frequency; 0.45-MPa in situ peak negative pressure; 100-cycle pulse length; 1-kHz pulse repetition frequency; 60-s exposure period). Using flow cytometry, we found that sonoporated cells exhibited a progressive loss of functional ER mass over a 6-h period. Also, post-exposure Western blot assays (between 0 and 24 h) revealed various indications of post-sonoporation ER stress: (i) upregulation of ER-resident enzymes responsible for catalyzing protein folding; (ii) activation of trans-ER-membrane stress sensors; (iii) increased expression of ER-induced regulatory proteins that mediate pro-apoptotic signals to the mitochondria. These results corresponded to flow cytometry observations that depicted a progressive depolarization of a sonoporated cell's mitochondrial outer membrane potential. They were also consistent with another Western blot assay that found, in sonoporated cells, a time-lapse increase of caspase-9 (a mitochondria-activated apoptosis initiator protein). Taken together, our findings indicate that sonoporation may upset ER homeostasis, and this may ultimately result in initiation of apoptosis.
Original language | English |
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Journal | Ultrasound in Medicine and Biology |
Volume | 39 |
Issue number | 12 |
Pages (from-to) | 2382-2392 |
Number of pages | 11 |
ISSN | 0301-5629 |
DOIs | |
Publication status | Published - Dec 2013 |
Bibliographical note
Funding Information:
This work is funded in part by the Hong Kong Innovation and Technology Fund ( ITS/292/11 ) and the National Science Foundation of China ( 81201098 ).
- Apoptosis, Endoplasmic reticulum, Mitochondria, Signaling pathway, Sonoporation, Stress response
Research areas
ID: 299106573