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J. Biol. Chem., Vol. 281, Issue 19, 13694-13707, May 12, 2006

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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^*

From the Department of Pathology, Duke University, Medical Center, Durham, North Carolina 27710

Binding of activated forms of the proteinase inhibitor ₂-macroglobulin (₂M^*) 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-Bin ₂M^*-induced proliferation of 1-LN cells. Exposure of cells to ₂M^* (50 pM) induced phosphatidylinositol 3-kinase-dependent activation of Akt by phosphorylation at Thr-308 and Ser-473 with a concomitant 60-80% increase in Akt-associated 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^* down-regulated apoptosis and promoted NF-B activation as shown by increases of Bcl-2, p-Bad^Ser-136, p-FOXO1^Ser-253, p-GSK3^Ser-9, XIAP, NF-B, cyclin D1, GADD45, p-ASK1^Ser-83, and TRAF2 in a time of incubation-dependent manner. ₂M^* 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, and GADD34 and reduced levels of GADD153. Silencing of GRP78 gene expression by RNAi suppressed activation of Akt^Thr-308, Akt^Ser-473, and IB kinase kinase. The effects of ₂M^* on the NF-B activation, antiapoptotic signaling, unfolded protein response signaling, and proapoptotic signaling were also reversed by this treatment. In conclusion, ₂M^* 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.

Received for publication, October 28, 2005 , and in revised form, March 15, 2006.

^* This work was supported by NHLBI, National Institutes of Health, Grant HL-24066. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pathology, Box 3712, Duke University Medical Center, Durham, NC 27710. Tel.: 919-684-3528; Fax: 919-684-8689; E-mail: Pizzo001{at}mc.duke.edu.

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