TY - JOUR
T1 - DHA induces apoptosis by altering the expression and cellular location of GRP78 in colon cancer cell lines
AU - Fasano, Elena
AU - Serini, Simona
AU - Piccioni, Elisabetta
AU - Toesca Di Castellazzo, Amelia
AU - Monego, Giovanni
AU - Cittadini, Achille Renato Maria
AU - Ranelletti, Franco Oreste
AU - Calviello, Gabriella
PY - 2012
Y1 - 2012
N2 - n−3 polyunsaturated fatty acids exert growth-inhibitory and pro-apoptotic effects in colon cancer cells. We
hypothesized that the anti-apoptotic glucose related protein of 78 kDa (GRP78), originally described as a
component of the unfolded protein response in endoplasmic reticulum (ER), could be a molecular target
for docosahexaenoic acid (DHA) in these cells. GRP78 total and surface overexpression was previously associated
with a poor prognosis in several cancers, whereas its down-regulation with decreased cancer growth
in animal models. DHA treatment induced apoptosis in three colon cancer cell lines (HT-29, HCT116 and
SW480), and inhibited their total and surface GRP78 expression. The cell ability to undergo DHA-induced apoptosis
was inversely related to their level of GRP78 expression. The transfection of the low GRP78-expressing
SW480 cells with GRP78-GFP cDNA significantly induced cell growth and inhibited the DHA-driven apoptosis,
thus supporting the essential role of GRP78 in DHA pro-apoptotic effect. We suggest that pERK1/2 could be the
first upstream target for DHA, and demonstrate that, downstream of GRP78, DHA may exert its proapoptotic
role by augmenting the expression of the ER resident factors ERdj5 and inhibiting the phosphorylation of
PKR-like ER kinase (PERK), known to be both physically associated with GRP78, and by activating caspase-4.
Overall, the regulation of cellular GRP78 expression and location is suggested as a possible route through
which DHA can exert pro-apoptotic and antitumoral effects in colon cancer cells.
AB - n−3 polyunsaturated fatty acids exert growth-inhibitory and pro-apoptotic effects in colon cancer cells. We
hypothesized that the anti-apoptotic glucose related protein of 78 kDa (GRP78), originally described as a
component of the unfolded protein response in endoplasmic reticulum (ER), could be a molecular target
for docosahexaenoic acid (DHA) in these cells. GRP78 total and surface overexpression was previously associated
with a poor prognosis in several cancers, whereas its down-regulation with decreased cancer growth
in animal models. DHA treatment induced apoptosis in three colon cancer cell lines (HT-29, HCT116 and
SW480), and inhibited their total and surface GRP78 expression. The cell ability to undergo DHA-induced apoptosis
was inversely related to their level of GRP78 expression. The transfection of the low GRP78-expressing
SW480 cells with GRP78-GFP cDNA significantly induced cell growth and inhibited the DHA-driven apoptosis,
thus supporting the essential role of GRP78 in DHA pro-apoptotic effect. We suggest that pERK1/2 could be the
first upstream target for DHA, and demonstrate that, downstream of GRP78, DHA may exert its proapoptotic
role by augmenting the expression of the ER resident factors ERdj5 and inhibiting the phosphorylation of
PKR-like ER kinase (PERK), known to be both physically associated with GRP78, and by activating caspase-4.
Overall, the regulation of cellular GRP78 expression and location is suggested as a possible route through
which DHA can exert pro-apoptotic and antitumoral effects in colon cancer cells.
KW - Docosahexaenoic acid
KW - GRP78
KW - apoptosis
KW - colon cancer
KW - Docosahexaenoic acid
KW - GRP78
KW - apoptosis
KW - colon cancer
UR - http://hdl.handle.net/10807/28892
U2 - 10.1016/j.bbadis.2012.08.003
DO - 10.1016/j.bbadis.2012.08.003
M3 - Article
SN - 0925-4439
VL - 2012
SP - 1762
EP - 1772
JO - BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR BASIS OF DISEASE
JF - BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR BASIS OF DISEASE
ER -