eCite Digital Repository
Interplay between Endoplasmic Reticular Stress and Survivin in Colonic Epithelial Cells
Citation
Gundamaraju, R and Vemuri, R and Chong, WC and Myers, S and Norouzi, S and Shastri, MD and Eri, R, Interplay between Endoplasmic Reticular Stress and Survivin in Colonic Epithelial Cells, Cells, 7, (10) Article 171. ISSN 2073-4409 (2018) [Refereed Article]
![]() | PDF 633Kb |
Copyright Statement
© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Abstract
Sustained endoplasmic reticular stress (ERS) is implicated in aggressive metastasis of
cancer cells and increased tumor cell proliferation. Cancer cells activate the unfolded protein
response (UPR), which aids in cellular survival and adaptation to harsh conditions. Inhibition of
apoptosis, in contrast, is a mechanism adopted by cancer cells with the help of the inhibitor of an
apoptosis (IAP) class of proteins such as Survivin to evade cell death and gain a proliferative
advantage. In this study, we aimed to reveal the interrelation between ERS and Survivin. We
initially verified the expression of Survivin in Winnie (a mouse model of chronic ERS) colon tissues
by using immunohistochemistry (IHC) and immunofluorescence (IF) in comparison with wild type
Blk6 mice. Additionally, we isolated the goblet cells and determined the expression of Survivin by
IF and protein validation. Tunicamycin was utilized at a concentration of 10 µg/mL to induce ERS
in the LS174T cell line and the gene expression of the ERS markers was measured. This was followed
by determination of inflammatory cytokines. Inhibition of ERS was carried out by 4Phenyl Butyric
acid (4PBA) at a concentration of 10 mM to assess whether there was a reciprocation effect. The
downstream cell death assays including caspase 3/7, Annexin V, and poly(ADP-ribose) polymerase
(PARP) cleavage were evaluated in the presence of ERS and absence of ERS, which was followed by
a proliferative assay (EdU click) with and without ERS. Correspondingly, we inhibited Survivin by
YM155 at a concentration of 100 nM and observed the succeeding ERS markers and inflammatory
markers. We also verified the caspase 3/7 assay. Our results demonstrate that ERS inhibition not
only significantly reduced the UPR genes (Grp78, ATF6, PERKandXBP1) along with Survivin but
also downregulated the inflammatory markers such as IL8, IL4, and IL6, which suggests a positive
correlation between ERS and the inhibition of apoptosis. Furthermore, we provided evidence that
ERS inhibition promoted apoptosis in LS174T cells and shortened the proliferation rate. Moreover,
Survivin inhibition by YM155 led to a comparable effect as that of ERS inhibition, which includes
attenuation of ERS genes and inflammatory markers as well as the promotion of programmed cell
death via the caspase 3/7 pathway. Together, our results propose the interrelation between ERS and
inhibition of apoptosis assigning a molecular and therapeutic target for cancer treatment.
Item Details
Item Type: | Refereed Article |
---|---|
Keywords: | endoplasmic reticular stress, apoptosis, survivin, unfolded protein response, inhibition of apoptosis, proliferation, Winnie, LS174T, colon, colon cancer, 4PBA, tunicmycin |
Research Division: | Biological Sciences |
Research Group: | Biochemistry and cell biology |
Research Field: | Cell metabolism |
Objective Division: | Health |
Objective Group: | Clinical health |
Objective Field: | Clinical health not elsewhere classified |
UTAS Author: | Gundamaraju, R (Mr Rohit Gundamaraju) |
UTAS Author: | Vemuri, R (Mr Ravichandra Vemuri) |
UTAS Author: | Chong, WC (Mr Wai Chong) |
UTAS Author: | Myers, S (Dr Stephen Myers) |
UTAS Author: | Norouzi, S (Mrs Shaghayegh Norouzi) |
UTAS Author: | Shastri, MD (Mr Madhur Shastri) |
UTAS Author: | Eri, R (Associate Professor Raj Eri) |
ID Code: | 128806 |
Year Published: | 2018 |
Web of Science® Times Cited: | 6 |
Deposited By: | Health Sciences |
Deposited On: | 2018-10-16 |
Last Modified: | 2018-11-30 |
Downloads: | 51 View Download Statistics |
Repository Staff Only: item control page