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Hyperactivated JNK Is a Therapeutic Target in Pvhl-Deficient Renal Cell Carcinoma

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Hyperactivated JNK Is a Therapeutic Target in Pvhl-Deficient Renal Cell Carcinoma Published OnlineFirst February 7, 2013; DOI: 10.1158/0008-5472.CAN-12-2362 Cancer Therapeutics, Targets, and Chemical Biology Research Hyperactivated JNK Is a Therapeutic Target in pVHL-Deficient Renal Cell Carcinoma Jiabin An1,3, Huiren Liu1,3, Clara E. Magyar4, Yanchuan Guo7, Mysore S. Veena2,5, Eri S. Srivatsan2,5, Jiaoti Huang4, and Matthew B. Rettig1,3,6 Abstract Clear cell renal cell carcinomas (RCC), the major histologic subtype of RCC accounting for more than 80% of cases, are typified by biallelic inactivation of the von Hippel–Lindau (VHL) tumor suppressor gene. Although accumulation of hypoxia-inducible factor alpha (HIF-a) is the most well-studied effect of VHL inactivation, direct inhibition of HIFa or restoration of wild-type pVHL protein expression has not proved readily feasible, given the limitations associated with pharmacologic targeting of transcription factors (i.e., HIF-a) and gene replacement therapy of tumor suppressor genes (i.e., VHL). Here, we have established that phosphorylated c-Jun, a substrate of the c-Jun-NH2-kinase (JNK), is selectively activated in clear cell RCC patient specimens. Using multiple isogenic cell lines, we show that HIF-a–independent JNK hyperactivation is unique to the pVHL-deficient state. Importantly, pVHL-deficient RCCs are dependent upon JNK activity for in vitro and in vivo growth. A multistep signaling pathway that links pVHL loss to JNK activation involves the formation of a CARD9/BCL10/TRAF6 complex as a proximal signal to sequentially stimulate TAK1 (MAPKKK), MKK4 (MAPKK), and JNK (MAPK). JNK stimulates c-Jun phosphorylation, activation, and dimerization with c-Fos to form a transcriptionally competent AP1 complex that drives transcription of the Twist gene and induces epithelial–mesenchymal transition. Thus, JNK represents a novel molecular target that is selectively activated in and drives the growth of pVHL-deficient clear cell RCCs. These findings can serve as the preclinical foundation for directed efforts to characterize potent pharmacologic inhibitors of the JNK pathway for clinical translation. Cancer Res; 73(4); 1–12. Ó2012 AACR. Introduction devoid of VHL gene alterations and express wild-type pVHL (2). The protein product of the VHL gene, pVHL, serves many Reexpression of pVHL suppresses tumor formation in pVHL- fi a functions, the most well-characterized of which relate to its de cient murine models (3), and HIF- expression is required fi role in the E3 ligase complex that polyubiquitinates the tran- for tumorigenesis in the context of pVHL de ciency (4, 5). scription factor, hypoxia-inducible factor alpha (HIF-a), there- Thus, there is a preclinical rationale for drug development – a by marking it for proteasome-mediated degradation (1). In this aimed at inhibition of the pVHL HIF interaction. Unfortu- fi VHL capacity, pVHL plays a central role in mammalian cellular nately, ef cient and selective restoration of the gene in responses to ambient oxygen tension. Biallelic inactivation of tumor cells of actual patients is not achievable with current the VHL gene characterizes both hereditary and sporadic forms gene therapy technologies, and transcription factors such as a of clear cell renal cell carcinoma (RCC). Approximately 90% of HIF- are not readily amenable to drug development. There- – a clear cell RCCs manifest biallelic VHL inactivation through fore, despite the etiologic role of the pVHL HIF relationship genetic and epigenetic mechanisms, whereas nonclear cell in renal carcinogenesis, alternative strategies aimed at target- RCC variants such as papillary and chromophobe RCCs are ing more traditional "druggable" targets are required. In the case of clear cell RCC, proto-oncoproteins that are negatively regulated by pVHL may recapitulate the state of nononcogene addiction under the conditions of biallelic VHL fi 1 Authors' Af liations: Department of Medicine, Division of Hematology- inactivation. That is, the identification of biochemical signals, Oncology and 2Department of Surgery, VA Greater Los Angeles Healthcare System; Departments of 3Urology, 4Pathology and Laboratory Medicine, especially "druggable" kinases that are activated in response to 5Surgery, and 6Medicine, Division of Hematology-Oncology, David Geffen VHL loss in a HIF-a–independent fashion could provide alter- School of Medicine at UCLA, Los Angeles, California; and 7Technical Institute of Physics and Chemistry, Chinese Academy of Science, Beijing, native opportunities for therapeutic development. Indeed, China there is evidence for the existence of HIF-a–independent Note: Supplementary data for this article are available at Cancer Research effects of pVHL. For example, pVHL regulates an inhibitory Online (http://cancerres.aacrjournals.org/). phosphorylation of caspase recruitment domain 9 protein Corresponding Author: Matthew B. Rettig, UCLA VAGLAHS, 11301 (CARD9) by CK2 and downregulates activated PKC activity Wilshire Blvd, Bldg. 500, Room 4237, Los Angeles, CA, 90073. Phone: (6, 7). Important genotype–phenotype correlations in the 310-794-3565; Fax: 310-268-4508; E-mail: [email protected] subtypes of von Hippel–Lindau syndrome provide further doi: 10.1158/0008-5472.CAN-12-2362 evidence for HIF-a–independent effects of pVHL. In type 2C Ó2012 American Association for Cancer Research. von Hippel–Lindau syndrome, the associated VHL mutations www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst February 7, 2013; DOI: 10.1158/0008-5472.CAN-12-2362 An et al. do not lead to HIF-a dysregulation, yet patients develop stain. The accuracy of thresholding was verified by a licensed pheochromocytomas (8). Thus, biochemical and clinical cor- pathologist before analysis. For assessing nuclear staining, relative evidence points to the existence of HIF-a–independent positive 3,30-diaminobenzidine staining was calculated by effects of pVHL that are germane to oncogenesis. applying 2 color thresholds with one recognizing blue back- The c-Jun-NH2-kinase (JNK) is a mitogen-activated protein ground (hematoxylin stained) cells and another recognizing kinase (MAPK) required for Ras-induced transformation (9). It brown-positive cells and blue, nonpositive cells (total cell is protumorigenic in many tumor model systems. Its effects are number). Individual cells were discriminated by incorporating principally mediated through phosphorylation of members of the shape and size thresholds, providing, together with the the AP1 family of transcription factors, such as c-Jun (10). JNK color thresholds, actual cell counts. Percent of positivity was shares common upstream activators with components of the determined by dividing the cell number detected by the brown classical NF-kB pathway, which is constitutively activated in threshold by the total cell number, detected by the sum of the VHL-inactivated clear cell RCC in an HIF-a–independent brown and blue thresholds. Total tissue area analyzed was also manner. Accordingly, we investigated the potential for JNK to included in the final analysis. All investigations involving function in a nononcogene addiction fashion in the context of human specimens were carried out in accordance with the pVHL deficiency. principles of the Declaration of Helsinki. Materials and Methods Cell growth assay Reagents The MTT assay was conducted as described (17). The isogenic pairs of ACHN, SN12C, 786-0, UOK121, and UMRC6 cell lines have been described (11, 12). The ACHN and Statistical analyses SN12C isogenic pairs were obtained from George Thomas Data are presented as mean Æ SD. Significance was deter- (Oregon Health Sciences University, Portland, OR) and were mine with a 2-tailed Student t test. tested for pVHL and HIF-a expression by Western blotting (Supplementary Fig. S1). The 786-0 cell lines were obtained Results from W. Kaelin (Dana Farber Cancer Institute, Boston, MA); Activation of c-Jun in human clear cell RCC specimens UOK121 cells were from J. Gnarra (Louisiana State University, We first assessed the state of JNK/AP1 activation in the Baton Rouge, LA); and UMRC6 cells were from B. Zbar context of pVHL deficiency in human tissue by examining the (National Cancer Institute, Bethesda, MD). The 786-0, UOK121, extent of c-Jun phosphorylation by immunohistochemical and UMRC6 isogenic pairs of cell lines were originally tested for staining in clear cell versus nonclear cell RCC radical nephrec- pVHL and HIF-a expression by Western blotting as described tomy specimens. Here, we used a phospho-specific antibody earlier and are retested quarterly (12). The TRAF6-DN was used that detects c-Jun when phosphorylated at serine 73, a residue as described (13). Lentiviral plasmids designed to express that is a substrate for JNK phosphorylation and thus is marker target-specific or non-silencing (NS) short hairpin RNA (shRNA) for JNK activity (18–20). Quantitative assessment by image were obtained from Open Biosystems, as was the Twist lentiviral analysis confirmed that the percentage of cells exhibiting nu- plasmid. Transduction of a pVHL-resistant HIF-1a mutant clear p-c-Jun staining was statistically significantly greater (P ¼ À (P402A;P564A) or HIF-2a mutant (P405A;P531A) expressed in 7.2 Â 10 23) in clear cell RCCs than in the nonclear cell þ the pBabe retrovirus was used to express HIF-a in VHL cells counterparts (Fig. 1A and B and Supplementary Table S1). (14, 15). The pRL-SV40 Renilla luciferase reporter for normal- The marked difference in p-c-Jun staining was preserved when ization
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