Abstract
Dormant cancer cells are starvation-resistant leading to problems in the management of cancer. In renal cell carcinomas (RCCs), starvation-resistant cells are resistant to various currently available therapies. However, targeting hypoxia inducible factor 2-alpha (HIF2-alpha) induces cell death in dormant-like/starvation-resistant RCCs. This study showed that the apoptotic cell death caused by tumor necrosis factor (TNF)-related apoptosis-induced ligand (TNFSF10/TRAIL) was attenuated by CASP8 and FADD-like apoptosis regulator (CFLAR/c-FLIP) following HIF2-alpha activation, despite the high expression of TRAIL in such RCCs. Knockdowns of TRAIL averted apoptotic cell death caused by HIF2-alpha inhibition in starvation-resistant RCCs. Knockdowns of both HIF2-alpha and c-FLIP augmented apoptotic cell death, whereas overexpression of c-FLIP completely averted apoptosis. In addition, high abundance of TRAIL was correlated with poor prognosis in patients with RCC, suggesting that TRAIL, followed by HIF2-alpha and c-FLIP, play a role in the survival and/or progression of malignant RCCs.
Highlights
Renal cell carcinoma (RCC) is the urological malignancy with the highest rate of mortality and an increasing incidence worldwide [1]
TRAIL up-regulation was generally confirmed in starvation-resistant RCCs, in which cell death was induced by inhibiting HIF2-alpha, compared with those of starvation-sensitive RCCs, with the exception of Caki1 (Figure 1C and 1D)
These results suggested that TNFSF10 may contribute to the mechanism of cell death caused by inhibiting HIF2-alpha in dormant-like/ starvation-resistant RCC
Summary
Renal cell carcinoma (RCC) is the urological malignancy with the highest rate of mortality and an increasing incidence worldwide [1]. Starvation-sensitive RCCs produce N-linked (ß-N-acetylglucosamine)2 [N-GlcNAc2]modified glycoproteins [7, 8] These glycoproteins promoted cell death via unfolded protein responses in the endoplasmic reticulum [7, 9]. Starvationresistant RCCs tolerated the deprivation condition without cytotoxic unfolded protein responses [7], and survived using their enhanced mitochondrial performance and sources of stored carbons [10]. The behavior of the latter type is similar to that of dormant cancer cells, which are often problematic during the therapeutic management of RCC. Targeting HIF2-alpha induces cell death in the latter dormant-like RCC [11] (Supplementary Table 1)
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