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Loss of cell surface TFII‐I promotes apoptosis in prostate cancer cells stimulated with activated α2‐macroglobulin*

Receptor‐recognized forms of α2‐macroglobulin (α2M*) bind to cell surface‐associated GRP78 and initiate pro‐proliferative and anti‐apoptotic signaling. Ligation of GRP78 with α2M* also upregulates TFII‐I, which binds to the GRP78 promoter and enhances GRP78 synthesis. In addition to its transcriptional functions, cytosolic TFII‐I regulates agonist‐induced Ca2+ entry. In this study we show that down regulation of TFII‐I gene expression by RNAi profoundly impairs its cell surface expression and anti‐apoptotic signaling as measured by significant reduction of GRP78, Bcl‐2, and cyclin D1 in 1‐Ln and DU‐145 human prostate cancer cells stimulated with α2M*. In contrast, this treatment significantly increases levels of the pro‐apoptotic proteins p53, p27, Bax, and Bak and causes DNA fragmentation. Furthermore, down regulation of TFII‐I expression activates agonist‐induced Ca2+ entry. In plasma membrane lysates p‐PLCγ1, TRPC3, GRP78, MTJ1, and caveolin co‐immunoprecipitate with TFII‐I suggesting multimeric complexes of these proteins. Consistent with this hypothesis, down regulating TFII‐I, MTJ1, or GRP78 expression by RNAi greatly attenuates cell surface expression of TFII‐I. In conclusion, we demonstrate that not only does cell surface GRP78 regulate apoptosis, but it also regulates Ca2+ homeostasis by controlling cell surface localization of TFII‐I. J. Cell. Biochem. 112: 1685–1695, 2011. © 2011 Wiley‐Liss, Inc.