The interplay between GRP78 expression and Akt activation in human colon cancer cells under celecoxib treatment

Abstract

It has been reported previously that celecoxib shows antitumor effects in many types of cancers. Here, we detected its effects on DLD-1 and SW480 (two human colon cancer cell lines) and investigated the dynamic relationship between the 78-kDa glucose-regulatory protein (GRP78) and the phosphoinositide 3-kinase (PI3K)/Akt pathway. Gene expression was detected by real-time PCR and western blot analysis; the cytotoxicity was determined by the MTT assay and flow cytometry. First, the results showed that celecoxib induced cytotoxicity in a dose-dependent and time-dependent manner. Furthermore, we found the celecoxib-triggered unfolded protein response and the bidirectional regulation of Akt activation in both cell lines. Inhibiting the Akt activation by the PI3K inhibitor LY294002 markedly enhanced GRP78 expression. Besides, silencing the GRP78 expression regulated Akt activation in a time-dependent manner and increased the induction of the C/EBP homologous protein (CHOP) as well as considerably promoted celecoxib-induced apoptosis. In conclusion, these findings provide evidence that under the celecoxib treatment, GRP78 plays a protective role by modulating Akt activation and abrogating CHOP expression. However, Akt activation can provide a feedback loop to inhibit GRP78 expression. These studies can lead to novel therapeutic strategies for human colon cancer.

GRP78: A cell's response to stress

“…If AKT expression is reduced in GRP78overexpressing breast cancer cells, their sensitivity to gemcitabine increases and apoptosis also increases [88]. These results are in agreement with other types of cancers such as colon cancer [92], and prostate cancer [93].…”

ADAM17-siRNA inhibits MCF-7 breast cancer through EGFR-PI3K-AKT activation

“…PI3K, a heterodimer made up of a p110 catalytic subunit and a p85 regulatory subunit, has been confirmed to phosphorylate the serine/threonine kinase (AKT) (31). As a downstream effector of PI3K, AKT is closely related to cell survival and anti-apoptotic signaling (32,33). A recent study proved that cell signaling is mediated by PI3K-AKT through induction of ADAM17, which is involved in proliferation and migration of cancer cells (14).…”

GRP78 targeting: Hitting two birds with a stone

“…1 ) [ 4 , 24 ]. This CS-GRP78 characterizes many aggressive types of cancers such as breast, ovarian, pancreatic, and colon cancers [ 4 , 16 , 17 , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] ]. Additionally, CS-GRP78 was reported to facilitate pathogenic entry, both viral and fungal infections.…”

“…The overexpressed GRP78 on the cell surface is the primary reason for the radio-resistance in NSCLC and GBM [ 54 ]. Targeting cell-surface GRP78 enhances the apoptosis and reduces cell proliferation, colony formation, and downregulates the crucial intracellular phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling essential in the cell cycle, growth and survival [ 25 , 30 , 31 ]. Besides, tumor growth is delayed with enhanced efficacy of the radiation treatment upon anti-GRP78 antibody administration in mice [ 54 ].…”