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Papers In Press, published online ahead of print March 16, 2006
Dept. of Pathology, Duke University Medical Center, Durham, NC 27710
Corresponding Author: Pizzo001{at}mc.duke.edu
Binding of activated forms of the proteinase inhibitor
J. Biol. Chem, 10.1074/jbc.M511694200
Submitted on October 28, 2005
Accepted on March 16, 2006
Activation and cross talk between AKT, NF
B, and unfolded protein response signaling in 1-LN prostate cancer cells consequent to ligation of cell surface-associated GRP78
2-macroglobulin (2*)1 to cell surface-associated GRP78 on 1-LN human prostate cancer cells causes their proliferation. We have now examined the interplay between Akt activation, regulation of apoptosis, the unfolded protein response, and activation of NF
B in 2*-induced proliferation of 1-LN cells. Exposure of cells to 2M* (50 pM) induced PI 3-kinase-dependent activation of Akt by phosphorylation at Thr308 and Ser473 with a concomittant 60 to 80% increase in Akt-associate kinase activity. ERK1/2 and p38 MAPK were also activated, but there was only a marginal effect on JNK activation. Treatment of 1-LN cells with 2M* downregulated apoptosis and promoted NFB activation as shown by increases of Bcl-2, p-BadSer136, p-FOXO1Ser253, p-GSK3ßSer9, XIAP, NFB, cyclin D1, GADD45ß, p-ASK1Ser83, and TRAF2 in a time of incubation-dependent manner. 2* treatment of 1-LN cells; however, showed no increase in the activation of caspase-3, 9, or 12. Under these conditions, we observed increased unfolded protein response signaling as evidenced by elevated levels of GRP78, IRE1, XBP-1, ATF4, ATF6, p-PERK, p-eIF2, GADD34, and reduced levels of GADD153. Silencing of GRP78 gene expression by RNAi suppressed activation of AktThr308, AktSer473, and IKK kinase. The effects of 2M* on the NFB activation, anti-apoptotic signaling, UPR signaling, and pro-apoptotic signaling were also reversed by this treatment. In conclusion, 2* promotes cellular proliferation of 1-LN prostate cancer cells by activating MAPK and Akt-dependent signaling, down regulating apoptotic signaling, and activating unfolded protein response signaling.
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