Dataset Information

A pilot study on morphology and the mechanism involved in linearly patterned programmed cell necrosis in melanoma.

ABSTRACT: Accumulating data provide evidence that autophagy contributes to programmed cell death (PCD) under certain circumstances. Immunohistochemistry and real-time PCR were performed to investigate the correlation the expression of autophagy-related proteins LC3 and Atg4B and linearly patterned programmed cell necrosis (LPPCN) in melanoma. LPPCN was recently reported to be a special PCD, which is similar to neither apoptosis nor conventional necrosis commonly observed in tumoral tissues. The mechanism involved in LPPCN remains unclear. Our data showed that the expression of LC3 and Atg4B in the LPPCN-positive group was significantly higher than that in the LPPCN-negative group regarding protein and mRNA levels (p<0.05). Based on morphological observation, immunohistochemistry and real-time PCR experiments in this study, it was concluded that autophagy may play a crucial role in the process of LPP+CN in melanoma. This study provides novel insights into the mechanism that regulates LPPCN in vivo during tumor development. We speculated that LPPCN may be an early stage event in tumoral neovascularization under hypoxic-microenvironmental conditions. Accordingly, LPPCN can be considered a novel target in the process of antiangiogenesis treatment, which can be expected to obtain a better clinical outcome in the future.

SUBMITTER: Han C

PROVIDER: S-EPMC3436356 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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A pilot study on morphology and the mechanism involved in linearly patterned programmed cell necrosis in melanoma.

Han Chunrong C Sun Baoc Un BU Wang Wei W Cai Wen Juan WJ Lou Dan D Sun Yan Y Zhao Xiulan X

Oncology letters 20100901 5

Accumulating data provide evidence that autophagy contributes to programmed cell death (PCD) under certain circumstances. Immunohistochemistry and real-time PCR were performed to investigate the correlation the expression of autophagy-related proteins LC3 and Atg4B and linearly patterned programmed cell necrosis (LPPCN) in melanoma. LPPCN was recently reported to be a special PCD, which is similar to neither apoptosis nor conventional necrosis commonly observed in tumoral tissues. The mechanism ...[more]

PMID: 22966387

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Project description:Altered metabolism is an important part of malignant transformation of tumor cells. Oncogenic transformation may reprogram tumor metabolism and render tumor cells addicted to extracellular nutrients. Such nutrient addictions associated with oncogenic mutations may offer therapeutic opportunities; however, it remains difficult to predict these nutrient addictions. Here, we performed a nutrigenetic screen to determine the phenotypes of isogenic pairs of clear-cell renal cancer cells (ccRCC) with or without VHL upon the deprivation of individual amino acids. We identified that cystine deprivation triggered rapid programmed necrosis in VHL-deficient RCC, but not in their VHL-restored counterparts. Similar cystine addiction was also observed in VHL-deficient primary RCC tumors cells. Blockage of cystine uptake significantly delayed xenograft growth of ccRCC. Importantly, cystine deprivation triggered similar metabolic changes regardless of VHL status. Therefore, metabolic differences due to cystine deprivation are not different enough to readily explain the distinct fate of life vs. death in VHL-deficient and restored cell.. Instead, we found that increased levels of TNFÎ± associated with VHL loss in the VHL-deficient RCC force them to rely on intact RIPK1 to inhibit apoptosis. However, this pre-existing elevated TNFÎ± in the VHL-deficient ccRCC renders these cells susceptible to the necrosis signaling triggered by cystine deprivation. In addition, we identified that cystine-deprived necrosis in VHL-deficient RCC depends on reciprocal amplification of the Src-p38-Noxa signaling and TNFÎ±-RIP1/3-MLKL necrosis pathways that culminate in MLKL oligomerization and programmed necrosis. Together, our data reveal that the contextual cystine-addictions in VHL-deficient ccRCC is dependent on activating pre-existing oncogenic pathways to trigger programmed necrosis. RNA was extracted by RNAeasy kits (Qiagen) from the RCC4 Vec and VHL-reconstituted cells which were exposed to the control full DMEM or cystine deprived DMEM media for 6 hours (three replicates in each condition).

Dataset Information

A pilot study on morphology and the mechanism involved in linearly patterned programmed cell necrosis in melanoma.

Publications

A pilot study on morphology and the mechanism involved in linearly patterned programmed cell necrosis in melanoma.

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