PTEN loss mediated Akt activation promotes prostate tumor growth and metastasis via CXCL12/CXCR4 signaling

Abstract

IntroductionThe chemokine CXCL12, also known as SDF-1, and its receptor, CXCR4, are overexpressed in prostate cancers and in animal models of prostate-specific PTEN deletion, but their regulation is poorly understood. Loss of the tumor suppressor PTEN (phosphatase and tensin homolog) is frequently observed in cancer, resulting in the deregulation of cell survival, growth, and proliferation. We hypothesize that loss of PTEN and subsequent activation of Akt, frequent occurrences in prostate cancer, regulate the CXCL12/CXCR4 signaling axis in tumor growth and bone metastasis.MethodsMurine prostate epithelial cells from PTEN+/+, PTEN+/−, and PTEN−/− (prostate specific knockdown) mice as well as human prostate cancer cell lines C4-2B, PC3, and DU145 were used in gene expression and invasion studies with Akt inhibition. Additionally, HA-tagged Akt1 was overexpressed in DU145, and tumor growth in subcutaneous and intra-tibia bone metastasis models were analyzed.ResultsLoss of PTEN resulted in increased expression of CXCR4 and CXCL12 and Akt inhibition reversed expression and cellular invasion. These results suggest that loss of PTEN may play a key role in the regulation of this chemokine activity in prostate cancer. Overexpression of Akt1 in DU145 resulted in increased CXCR4 expression, as well as increased proliferation and cell cycle progression. Subcutaneous injection of these cells also resulted in increased tumor growth as compared to neo controls. Akt1 overexpression reversed the osteosclerotic phenotype associated with DU145 cells to an osteolytic phenotype and enhanced intra-osseous tumor growth.ConclusionsThese results suggest the basis for activation of CXCL12 signaling through CXCR4 in prostate cancer driven by the loss of PTEN and subsequent activation of Akt. Akt1-associated CXCL12/CXCR4 signaling promotes tumor growth, suggesting that Akt inhibitors may potentially be employed as anticancer agents to target expansion of PC bone metastases.

PKB/Akt-dependent regulation of inflammation in cancer

“…Given the activating role of NF-κB by PKB, PKB may also control the expression of these chemokine receptors. Moreover, PKB activation induced by PTEN loss promotes prostate tumor growth and metastasis by up-regulating CXCR4 expression [78]. CXCR4 activation can further boost PKB activity [35,79].…”

Genomic Landscape of CXCR4 Mutations in Waldenström Macroglobulinemia

“…Mutation calling was performed using the torrent suite variant caller under the low stringency somatic settings (TS4.0). We have studied CXCR4 mutations along with MYD88 L265P (exon 5), CD79A (ITAM domain), CD79B (ITAM domain), CARD11 (exons [5][6][7][8][9], N-RAS (exons 2 and 3), K-RAS (exons 2 and 3), BRAF6 (exon 15), and PTEN (exon 5þ7) using NGS (n ¼ 53).…”

“…The SDF1/CXCR4 axis promotes activation of several pathways including RAS, Akt, and NF-kB and interplays with BCR pathway (6)(7)(8). The CXCR4 gene is located on the long arm of chromosome 2 at position 21 and codes for a chemokine receptor that promotes migration and survival of various B lymphoid malignancies (8)(9)(10).…”

Functional screen identifies kinases driving prostate cancer visceral and bone metastasis

“…SRC, BMX, and TNK2 kinases promote castration resistance by phosphorylating and stabilizing AR (20)(21)(22). Moreover, FGFR1, AKT1, and EGFR kinases activate pathways in prostate cancer cells to drive epithelial-to-mesenchymal transition and angiogenesis, both of which are key steps in metastasis (23)(24)(25). Despite the strong evidence implicating kinases in advanced prostate cancer, a systematic analysis of the functional role of kinases in prostate cancer metastasis has been lacking.…”