Intrinsic actions of IGFBP-3 and IGFBP-5 on Hs578T breast cancer epithelial cells: inhibition or accentuation of attachment and survival is dependent upon the presence of fibronectin

Abstract

The insulin-like growth factor binding proteins (IGFBPs) have IGF-independent differential effects on cell function. We investigated whether they can affect integrin-receptor-mediated cell attachment to different extracellular matrix (ECM) components in Hs578T cells.Cell attachment to a general ECM gel was unaffected by IGFBP-1 and -6 but was significantly increased by IGFBP-4 and -5 and decreased by IGFBP-2 and -3. Similar results were obtained for attachment to laminin or collagen type IV. Attachment to fibronectin, however, was increased by IGFBP-3 and decreased by IGFBP-5. The actions of IGFBP-3 and -5 on cell attachment to ECM were lost in the presence of a soluble Arg-Gly-Asp (RGD)-containing fibronectin fragment. Thrombospondin reversed the actions of IGFBP-3 on cell attachment, but IGFBP-5 still increased cell attachment.On plastic, neither IGFBP-3 nor -5 alone affected cell viability; although ceramide-induced apoptosis was enhanced by IGFBP-3 but reduced by IGFBP-5. The presence of RGD reversed the action of IGFBP-5 on cell death but attenuated that of IGFBP-3. With cells grown on fibronectin, the action of IGFBP-3 was reversed, and it conferred cell survival, whereas the survival effect of IGFBP-5 was lost.In summary we have demonstrated that IGFBP-3 and -5 both have intrinsic effects on cell survival. In each case the presence of fibronectin or fibronectin fragments determines whether susceptibility to apoptosis is increased or decreased. These effects on cell survival are paralleled by acute effects on integrin receptor function; IGFBP-3 and -5 were able to either enhance or inhibit cell attachment in the presence of fibronectin. Cell survival is tightly controlled by cues from the ECM and from growth factors, particularly the IGFs. Our findings indicate that, in addition to being crucial modulators of IGF actions, the IGFBPs have direct actions on cell attachment and survival that are specific and dependent upon the matrix components present.

IGFBP-3 Can Either Inhibit or Enhance EGF-mediated Growth of Breast Epithelial Cells Dependent upon the Presence of Fibronectin

“…On fibronectin, IGFBP-3 inhibited EGF-promoted growth of non-malignant cells but enhanced EGF-promoted growth of breast cancer cells. These results are entirely consistent with our previous work, which indicated that IGFBP-3 could reduce cell adhesion and accentuate apoptotic responses of breast cancer cells on laminin and collagen, but these effects were reversed on fibronectin (16). The ability of fibronectin to switch the actions of IGFBP-3 may account for the apparent ambiguity in the literature, relating to whether the presence of IGFBP-3 will have a positive or negative effect on breast cancer cells and adds to the evidence that integrins are critically involved in IGFBP-3 actions.…”

“…Fibronectin Reverses the Actions of IGFBP-3 on EGF-induced Cell Growth-We have shown previously that the ability of IGFBP-3 to modulate cell attachment and apoptosis was reversed in the presence of fibronectin (16). Therefore, we next assessed if the effects of IGFBP-3 on EGF-induced cell growth were similarly affected.…”

“…We went on to show that although IGFBP-3 could reduce cell attachment and enhance apoptosis of Hs578T breast cancer cells when these were cultured on plastic, collagen, or laminin, when the same cells were cultured on fibronectin, IGFBP-3 had the opposite effects and increased cell attachment and acted as a cell survival factor (16). Cholesterol-stabilized complexes are required for normal integrin signaling, and we showed that disrupting such complexes also reversed the intrinsic action of IGFBP-3 (5).…”

Phenotypes and genotypes of insulin-like growth factor 1, IGF-binding protein-3 and cancer risk: evidence from 96 studies

“…4 It was reported that IGFBP3 could play an anti-apoptotic role in Hs578T breast cancer cells. 43 Besides, body size, vigorous physical activity, and dietary factors could influence IGF1 and IGFBP3 molar ratio in pre-menopausal breast cancer women more than postmenopausal breast cancer women, 44 and they might account for the different roles of IGF1 and IGFBP3 in breast cancer according to menopausal status.…”

Apoptosis and disease: a matter of cell fate

“…Therefore, although the IGFBPs exert differential effects on malignant cells versus nonmalignant cells, whether apoptosis is inhibited or promoted in response to DNA damage can be totally reversed depending on the cell's interaction with extracellular matrix components. 34 This work sends us a message of caution in our eagerness to develop new apoptosis-based treatments -the environment in which the cell resides is a powerful modulator of apoptosis sensitivity.…”