A common genetic mutation found in clear cell renal cell carcinoma (CC-RCC) is the loss of the von Hippel-Lindau (VHL) gene, which results in stabilization of hypoxia-inducible factors (HIFs), and contributes to cancer progression and metastasis. CUB-domain-containing protein 1 (CDCP1) was shown to promote metastasis in scirrhous and lung adenocarcinomas as well as in prostate cancer. In this study, we established a molecular mechanism linking VHL loss to induction of the CDCP1 gene through the HIF-1/2 pathway in renal cancer. Also, we report that Fyn, which forms a complex with CDCP1 and mediates its signaling to PKCδ, is a HIF-1 target gene. Mechanistically, we found that CDCP1 specifically regulates phosphorylation of PKCδ, but not of focal adhesion kinase or Crk-associated substrate. Signal transduction from CDCP1 to PKCδ leads to its activation, increasing migration of CC-RCC. Furthermore, patient survival can be stratified by CDCP1 expression at the cell surface of the tumor. Taken together, our data indicates that CDCP1 protein might serve as a therapeutic target for CC-RCC.
The Cdc2L locus encoding the PITSLRE protein kinases maps to chromosome band 1p36 and consists of two duplicated and tandemly linked genes. The purpose of the present study was to determine whether diminution of PITSLRE kinases leads to deregulation of apoptosis. The human melanoma cell lines A375 (Cdc2L wild-type alleles) and UACC 1227 (mutant Cdc2L alleles) were tested with agonist anti-Fas monoclonal antibody. We found that exposure of these cells to anti-Fas for 24, 48, or 72 h resulted in differential sensitivity to Fasinduced apoptosis. In A375, cell death started at 24 -48 h post-treatment, and it was maximal by 72 h. Conversely, UACC 1227 cells were resistant to Fas-mediated apoptosis. Induction of PITSLRE histone H1 kinase activity was observed in A375 anti-Fas treated but not in UACC 1227 cells. Also, the PITSLRE protein kinase activity in A375 anti-Fas-treated cells preceded maximal levels of apoptosis. Finally, fluorescence confocal microscopy revealed a nuclear localization of PITSLRE proteins in normal melanocytes and A375 cells but a cytoplasmic localization in UACC 1227 cells. The differences in PITSLRE protein and cellular localization between A375 and UACC 1227 cells appear to account for the differences in sensitivity of the two cells lines to antiFas and staurosporine. These observations suggest that alterations in PITSLRE gene expression and protein localization may result in the loss of apoptotic signaling.
Skin cancer, which accounts for at least half of all cancers in the United States, is predicted to affects 1 in 5 Americans in their lifetime. Melanoma, the most serious form of skin cancer, is also the leading cause of all skin cancer deaths. This study demonstrates that AKAP12 (SSeCKS, AKAP250, gravin), a hypoxia-inducible scaffold protein, is considerably increased at the protein and RNA level in melanoma cell lines. In addition, there is a significant increase in RNA expression in primary and metastatic tumors when compared to normal specimens, as well as patients with poor prognosis, as measured by diminished 5- year survival. AKAP12 functions to dock many kinases and signaling proteins that regulate cell adhesion, spreading and migration, including: PKC, Src and F-actin. Since these processes are critical for tumor cell metastasis, we hypothesize that AKAP12 could be a central regulator of cancer progression. Stable knockdown of AKAP12 in two melanoma cell lines demonstrate decreases in invasion, migration and clonogenic potential in vitro, as well reduced colony forming abilities in conditions requiring anchorage-independent growth in soft agar. In vivo studies in a metastatic model of melanoma demonstrate a statistically significant decrease in tumors within the lungs of the AKAP12 knockdown groups, highlighting the importance of AKAP12 in metastatic disease. An orthotopic model also demonstrates decreased primary tumor growth and metastatic potential in mice injected with AKAP12 knocked down cells. Additionally, changes in cell morphology characteristic of increased motility and invasiveness are seen in cells containing AKAP12 but not those in which it had been knocked down. While this scaffold protein has been found to act as a tumor suppressor in several tissue types (lung, colon, prostate), we have uncovered its novel oncogenic properties in metastatic melanoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1460. doi:10.1158/1538-7445.AM2011-1460
Kidney cancer is the sixth leading cause of cancer death in the USA, and the primary tumor is frequently accompanied by metastasis to lungs, liver, brain and bones. Importantly a large number of kidney cancer cases are characterized by loss of von Hippel-Lindau (VHL) gene, which leads to stabilization of hypoxia-inducible factors (HIFs), which contribute to tumor progression and metastasis by multiple mechanisms. CUB-domain-containing protein 1 (CDCP1) was shown to be expressed on the cell surface of metastatic cell lines and to increase the number of nodules formed by lung adenocarcinoma cells and melanoma in lungs in tail vein injection experiments, enhance peritoneal dissemination of scirrhous adenocarcinoma, and to induce metastasis in the chicken embryo metastatic model. In the present study we investigated the role of CDCP1 protein in clear cell renal cell carcinoma (CC-RCC) and found it to be upregulated in this disease entity by a mechanism of VHL loss through HIFs. Interestingly, we found CDCP1 protein expressed not only on the membrane of kidney cancer cell lines, but also to be secreted into the media as a full length isoform. Importantly, in the knockdown experiments we found CDCP1 to promote CC-RCC cell migration in vitro, the process known to be the key during metastasis. Accordingly CDCP1 participates in the signal transduction pathway leading to PKCδ phosphorylation in CC-RCC, stimulating migration. The role of PKCδ in CDCP1-dependent migration was verified by the PKCδ knockdown experiments, which phenocopy the effect of CDCP1 knockdown; as well as migration rescue experiments, where the impairment of migration caused by CDCP1 downregulation was rescued by the overexpression of constitutively active mutant of PKCδ. Furthermore, we showed a correlation of CDCP1 cell surface expression in primary tumor with poor patient outcome. Finally, we found that suramin, a drug, which showed the clinical benefit for CC-RCC patients at premetastatic stages, causes the downregulation of CDCP1 at the protein level. Thus, the further investigation of the role of CDCP1 protein in kidney cancer metastasis is important to validate CDCP1 as a therapeutic target. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-357. doi:10.1158/1538-7445.AM2011-LB-357
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