Hormonal regulation of IGFBP‐2 proteolysis is attenuated with progression to androgen insensitivity in the LNCaP progression model

Abstract

The identification of molecular determinants involved in the promotion of metastasis and development of androgen insensitive prostate cancer (AI-PCa) is necessary to discriminate aggressive from indolent disease and to identify therapeutic targets for advanced disease. Overexpression of one particular member of the insulin like growth factor (IGF) axis, IGFBP-2, is implicated in the development of AI-PCa and other cancers. Using the LNCaP human PCa progression model, we show that the AI and metastatic prostate cancer cell line C4-2B4 expresses greater amounts of secreted IGFBP-2 than the androgen sensitive (AS), non-metastatic LNCaP progenitor cell line. Further, the ability of androgens to decrease extracellular IGFBP-2 levels is attenuated in the AI and metastatic C4-2 cell line. The ability of androgen to negatively regulate extracellular IGFBP-2 levels was blocked by Casodex in a dose-dependent manner. The mechanism underlying the androgen-induced downregulation of secreted IGFBP-2 appears to involve extracellular proteolysis, resulting in the production of IGFBP-2 fragments lacking the ability to bind IGF-I and IGF-II. As C4-2 cells have an attenuated ability to proteolyze IGFBP-2 in response to androgen and C4-2B4 cells express greater amounts of IGFBP-2, our data implies that the diminished regulation of IGFBP-2 and loss of associated proteolytic fragments play a role in the increased metastatic behavior of these cells in vivo. Furthermore, our results suggest that either increased levels of intact IGFBP-2 or decreased levels of IGFBP-2 proteolytic fragments could serve as a biomarker to monitor for progression to AI-PCa.

Role of Insulin-Like Growth Factor Binding Protein 2 in Lung Adenocarcinoma

“…IGFBP-2 protein is degraded by proteases such as matrix metalloprotease-1 and -7, calpain, as well as by basic fibroblast growth factor and an androgen blockade. [61][62][63][64] We found IGFBP-2 protein was degraded by a treatment of PI3K inhibitor in A549 cells. Because a various new PI3K inhibitors have been entered clinical trials, 65 IGFBP-2 would be a useful biomarker for the treatment with PI3K inhibitors in lung cancer as well as in glioma, prostate, and breast cancers.…”

Physiology and pathophysiology of IGFBP-1 and IGFBP-2 – Consensus and dissent on metabolic control and malignant potential

“…In addition to IGFBP-2 expression being associated with advanced prostate cancer and bone metastasis [102], IGFBP-2 also appears to be linked with the development of hormone refractory prostate cancer. As reported by DeGraff et al [103], androgen treatment in the LNCaP prostate cancer cell line (derived from metastatic site left supraclavicular Lymph Node; androgen sensitive; AS), initially increases the levels of IGFBP-2, but with extended androgen treatment levels, decreases via mechanisms likely to involve proteolysis of IGFBP-2. Interestingly, when the androgen insensitive (AI) and metastatic prostate cancer cell lines C4e2B4 and C4-2 (LNCaP derived) were investigated, it was found that these cells express a greater amount of IGFBP-2 and exhibit an attenuated ability to proteolyse extracellular IGFBP-2.…”

Loss of the Urothelial Differentiation Marker FOXA1 Is Associated with High Grade, Late Stage Bladder Cancer and Increased Tumor Proliferation

“…Western blotting analysis was performed as reported previously [25]. Briefly, cell lysates were prepared with Complete Lysis-M kit (Roche, Nutley NJ) as per manufacture protocol and protein concentrations were determined via standard BCA protocol (Pierce, Rockford, IL).…”