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

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

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

“…5A, full list of motifs in Supplementary Table S15). For subsequent in vitro validation, we chose c-Jun as a representative AP1 family member because of its activation in ccRCC (66) and ETS1 as an ETS family representative because of its known interaction with HIF2α (67), but acknowledge that other family AP1 and ETS family members may play a role in ccRCC. Immunoblotting of c-Jun, Research.…”

Mitogen-Activated Protein Kinases and Hypoxic/Ischemic Nephropathy

“…Although, it is also showed that JNK activity affects pVHL-deficient RCCs in in vitro and in vivo growth, JNK stimulates c-Jun phosphorylation, activation, and dimerization with c-Fos. This forms a transcriptionally competent activator protein-1 complex, which drives the transcription of the Twist gene and induces EMT, which is essential for renal tumor metastasis [130] …”

RASSF6promotes p21Cip1/Waf1-dependent cell cycle arrest and apoptosis through activation of the JNK/SAPK pathway in clear cell renal cell carcinoma

“…A model for the effect of RASSF6 on cell cycle and apoptosis in ccRCC is shown in Figure 7. RASSF6 inhibits the growth of both VHLdeficient (786-O) and VHL wild-type (SKRC39, ACHN) [29][30][31] cells, suggesting that RASSF6 may not depend on VHL status in ccRCC. The treatment strategy to enhance the inhibitory function of RASSF6 is promising in ccRCC, especially after treatment failure of targeting VHL.…”

“…Moreover, their abilities of tumor formation in nude mice have been repeatedly reported. [29][30][31] The ccRCC cell lines 786-O, SKRC39, and ACHN were maintained in RPMI 1640 medium (Invitrogen) supplemented with 10% fetal bovine serum (Invitrogen) at 37 °C and 5% CO 2 . To plot the cellular growth curve, 3 × 10 3 cells suspended in 200 μl of medium were seeded into a 96-well plate (Corning) and cultured under normal conditions.…”