Abstract
Progastrin (PG) exerts proliferative and antiapoptotic effects on intestinal epithelial and colon cancer cells via Annexin II (ANX-II). In here, we show that ANX-II similarly mediates proliferative and antiapoptotic effects of PG on a pancreatic cancer cell line, AR42J. The role of several signaling molecules was examined in delineating the biological activity of PG. PG (0.1-1.0 nmol/L) caused a significant increase (2- to 5-fold) in the phosphorylation of phosphatidylinositol 3-kinase (PI3K), Akt (Thr(308)), p38 mitogen-activated protein kinase (MAPK; Thr(180)/Tyr(182)), extracellular signal-regulated kinases (ERK; Thr(202)/Tyr(204)), IkappaB kinase alpha/beta (IKKalpha/beta; Ser(176)/(180)), IkappaBalpha (Ser(32)), and p65 nuclear factor-kappaB (NF-kappaB; Ser(536)). Inhibition of p44/42 ERKs (PD98059), p38 MAPK (SB203580), Akt, and PI3K (LY294002), individually or combined, partially reversed antiapoptotic effects of PG. The kinetics of phosphorylation of IKKalpha/beta in response to PG matched the kinetics of phosphorylation and degradation of IkappaBalpha and correlated with phosphorylation, nuclear translocation, and activation of p65 NF-kappaB. NF-kappaB essential modulator-binding domain peptide (an inhibitor of IKKalpha/beta) effectively blocked the activity of p65 NF-kappaB in response to PG. Activation of p65 NF-kappaB, in response to PG, was 70% to 80% dependent on phosphorylation of MAPK/ERK and PI3K/Akt molecules. Down-regulation of p65 NF-kappaB by specific small interfering RNA resulted in the loss of antiapoptotic effects of PG on AR42J cells. These studies show for the first time that the canonical pathway of activation of p65 NF-kappaB mediates antiapoptotic effects of PG. Therefore, targeting PG and/or p65 NF-kappaB may be useful for treating cancers, which are dependent on autocrine or circulating PGs for their growth.
Highlights
The full-length progastrin1-80 peptide (PG) is the precursor peptide of gastrin (G1-G17)
To confirm the role of Annexin II (ANX-II) in mediating growth effects of PG on AR42J cells, we examined the effect of anti-ANX-II and antiCCK2R antibodies (Fig. 1D)
Because activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (ERK) and phosphatidylinositol 3-kinase (PI3K)/Akt is reported to result in activation of nuclear factor-nB (NF-nB) [27], we examined if NF-nB is activated in response to PG via the canonical pathway involving phosphorylation of IKKa/h and degradation of InBa [27,28,29,30]
Summary
The full-length progastrin peptide (PG) is the precursor peptide of gastrin (G1-G17). PG and gastrin peptides exert growth effects on normal and cancerous intestinal epithelial cells (IEC) via PG-preferring receptors [2,3,4,5]. Doi:10.1158/0008-5472.CAN-07-1206 pancreatic cancer [6], lung cancer [7], and ovarian cancer [8] express the gastrin gene and PGs. It is possible that PG-like peptides play an important role in the growth and survival of many of these PG-expressing cancers as reported for PGdependent CRCs [2, 9]. Annexin II (ANX-II) was recently discovered as one such molecule and is required for mediating growth factor effects of PG/gastrin peptides on intestinal epithelial and colon cancer cells [11]. We confirmed if AR42J cells respond to proliferative and antiapoptotic effects of PG and if ANX-II mediates growth effects of PG on AR42J cells
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
