JAK kinases promote invasiveness in VHL-mediated renal cell carcinoma by a suppressor of cytokine signaling-regulated, HIF-independent mechanism

Abstract

Wu KL, Miao H, Khan S. JAK kinases promote invasiveness in VHL-mediated renal cell carcinoma by a suppressor of cytokine signaling-regulated, HIF-independent mechanism. Am J Physiol Renal Physiol 293: F1836-F1846, 2007. First published September 26, 2007; doi:10.1152/ajprenal.00096.2007 disease is a cancer syndrome, which includes renal cell carcinoma (RCC), and is caused by VHL mutations. Most, but not all VHL phenotypes are due to failure of mutant VHL to regulate constitutive proteolysis of hypoxia-inducible factors (HIFs). Janus kinases (JAK1, 2, 3, and TYK2) promote cell survival and proliferation, processes tightly controlled by SOCS proteins, which have sequence and structural homology to VHL. We hypothesized that in VHL disease, RCC pathogenesis results from enhanced SOCS1 degradation, leading to upregulated JAK activity. We find that baseline JAK2, JAK3, and TYK2 activities are increased in RCC cell lines, even after serum deprivation or coincubation with cytokine inhibitors. Furthermore, JAK activity is sustained in RCC stably expressing HIF2␣ shRNA. Invasion through Matrigel and migration in woundhealing assays, in vitro correlates of metastasis, are significantly greater in VHL mutant RCC compared with wild-type cells, and blocked by dominant-negative JAK expression or JAK inhibitors. Finally, we observe enhanced SOCS2/SOCS1 coprecipitation and reduced SOCS1 expression due to proteasomal degradation in VHLnull RCC compared with wild-type cells. The data support a new HIF-independent mechanism of RCC metastasis, whereby SOCS2 recruits SOCS1 for ubiquitination and proteasome degradation, which lead to unrestricted JAK-dependent RCC invasion. In addition to commonly proposed RCC treatment strategies that target HIFs, our data suggest that JAK inhibition represents an alternative therapeutic approach. Janus kinase; suppressor of cytokine signaling; von Hippel-Lindau syndrome VON HIPPEL-LINDAU (VHL) disease is a heritable multisystem cancer syndrome caused by germline mutations in VHL, which is located on chromosome 3p25 (30). The main causes of death are complications linked to highly angiogenic renal carcinomas and hemangioblastomas within the central nervous system (45, 59). The VHL gene is ubiquitously expressed (60) and the role of the VHL gene product (pVHL) in renal cell carcinoma (RCC) has been extensively studied (31, 49). There are currently no established, successful therapies, e.g., radiation or chemotherapy, for RCC other than nephrectomy in situations with no evidence of metastases.pVHL contains an ϳ100-residue NH 2 terminus (␤-domain) and a smaller COOH-terminal ␣-helix (␣-domain). Under normoxic conditions, the pVHL ␤-domain interacts with ␣-subunits of hypoxia-inducible factors (HIF)-1 and -2 transcription factors (48, 60), while the VHL ␣-domain and a small portion of the ␤-domain interact with Elongin C, a component of an E3 ubiquitin ligase complex that targets HIF-1␣ subunits for proteasomal degradation (31, 43, 64) and thereby prevents HIF transcription factor binding to target gene...

Inhibition of MDR1 in mammary cell carcinoma reverses Multidrug Resistance by SOCS1.

“…This result is similar to results from studies on renal cell carcinoma 23 and lung cancer, 24 indicating SOCS1 gene may be a tumor-suppressing gene and its downregulating expression may be correlated with breast cancer. In our study the expression rate of SOCS1 had no correlations with age, tumor size, lymph node metastasis, TNM stage, pathological type, ER and PR expression, which is consistent with the results of the study of Hao on gastric cancer.…”

Post-Transcriptional Fine-tuning of COP9 Signalosome Subunit Biosynthesis is Regulated by the c-Myc/Lin28B/let-7 Pathway

“…7a). Interferon-stimulated HeLa cells were treated with inhibitors of STAT1 signaling, the TYK2 inhibitor AG9 and JAK2-specific inhibitor AG490, 38 confirming that STAT1 mediated the observed effects. The mixture of both AG9 and AG490 was most effective in inhibiting the CSN1 and CSN8 biosynthesis (Fig.…”

Conditional inactivation of the mouse von Hippel–Lindau tumor suppressor gene results in wide-spread hyperplastic, inflammatory and fibrotic lesions in the kidney

“…32,33 Furthermore, JAK signaling is active in VHL mutant ccRCC cell lines. 34 Specifically, JAK2 expression is increased in VHL mutant ccRCC cell lines and has been shown to promote cell invasion, and this reaction is independent of HIF-2α. 34 Our findings are also supported by recent reports that implicated the VHL-HIF pathway in mediating inflammatory and fibrotic responses in vivo.…”