Involvement of Shc in the signaling response of human prostate tumor cell lines to epidermal growth factor

Abstract

Autocrine growth factors for the epidermal growth factor receptor (EGFR) have been identified in prostate tumors, implicating a role for EGFR in the progression of prostate cancer. To investigate early signaling mechanisms used by the EGFR in prostate tumor cells, we have characterized the involvement of the Shc (src homology 2/x‐collagen related) adapter protein in EGFR signaling in several human prostate tumor cell lines. In androgen‐responsive lymph node‐prostate cancer (LNCaP) cells and androgen‐insensitive PC3, DU145 and PPC‐1 cells, Shc was identified as one of the most prominent phosphotyrosine proteins to be elevated in response to EGF. Equivalent levels of the 46‐ and 52‐kDa Shc isoforms were detected in all of the tumor cell lines tested. However, levels of the 66‐kDa isoform were variable among the cell lines. In all of the tumor cell lines, EGF caused an association between Shc and Grb2, another adapter protein linked to cellular ras activation. Additionally, several phosphotyrosine proteins, including a 115–120‐kDa protein in EGF‐treated LNCaP cells, co‐associated with Shc. The profile of these Shc‐associating proteins, however, differed among the tumor cell lines. Our results indicate that Shc is a common downstream element of EGFR signaling in prostate tumor cells and suggest multiple functions for Shc in prostate tumorigenesis. Int. J. Cancer 77:923–927, 1998.© 1998 Wiley‐Liss, Inc.

Signaling via Shc family adapter proteins

“…For example, Shc has been identi®ed as one of the important molecules involved in BCR ± Abl mediated transformation (Goga et al, 1995). Moreover, Shc has been found to be hyperphosphorylated in several breast cancer lines and prostate cancer cells, and in some cases the proliferation of these transformed cells could be inhibited by overexpression of dominant negative proteins (Agarwal, 2000;Biscardi et al, 1998;Dankort et al, 2001;Gresham et al, 1998;Qiu et al, 1998;Rauh et al, 1999;Stevenson and Frackelton, 1998;Stevenson et al, 1999). Whether Shc provides a proliferative or survival signal under these conditions is not known, but it was suggestive that enhanced Shcmediated signaling was bene®cial in the growth or maintenance of the tumorigenic state.…”

p66Shc protein is upregulated by steroid hormones in hormone‐sensitive cancer cells and in primary prostate carcinomas

“…Alternatively, sex hormones may stabilize p66 Shc protein by altering its metabolic pathway including protein biosynthesis and/or degradation rate, resulting in an increased level of p66 Shc protein. Although the mechanism by which sex hormones raise p66 Shc protein level and cell growth rate remains to be elucidated, it is of interest that in androgen‐independent DU 145 cells, high basal level of p66 Shc protein is also correlated with rapid growth rate (unpublished observations) 29, 30. The same parallel can be drawn between our observation of a coordinated increase in p66 Shc levels and growth rate and the observation that the p66 Shc protein levels in human breast cancer correlate with increased metastatic potential 31…”

Apoptosis and Aging: Role of p66ShcRedox Protein

“…The Shc gene is related to cell proliferation and carcinogenesis (16,48). In fact the p52 Shc and p46 Shc isoforms of Shc were found to be overexpressed (5,8,56,58) or hyperphosphorylated (28,49) in many tumor types.…”

“…Indeed different levels of p66 Shc were found in some tumors but the results seem contradictory. For example, in breast cancer cells and primary tumors, p66 Shc was described to be both overexpressed (16,22,29) and downregulated (49,59). Indeed the ablation of p66 Shc does not increase spontaneous or induced tumor incidence in mice (32,51).…”