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ASPP2 enhances oxaliplatin (L-OHP)-induced colorectal cancer cell apoptosis in a p53-independent manner by inhibiting cell autophagy.

ABSTRACT: Inactivation of p53-mediated cell death pathways is a central component of cancer progression. ASPP2 (apoptosis stimulated protein of p53-2) is a p53 binding protein that specially stimulates pro-apoptosis function of p53. Down-regulation of ASPP2 is observed in many human cancers and is associated with poor prognosis and metastasis. In this study, ASPP2 was found to enhance L-OHP-induced apoptosis in HCT116 p53(-/-) cells in a p53-independent manner. Such apoptosis-promoting effect of ASPP2 was achieved by inhibiting autophagy. Further experiments with ASPP2 RNA interference and autophagy inhibitor (3-methyladenine, 3-MA) confirmed that ASPP2 enhanced HCT116 p53(-/-) cell apoptosis via inhibiting the autophagy. The association of cell death and autophagy was also found in ASPP2(+/-) mice, where colon tissue with reduced ASPP2 expression displayed more autophagy and less cell death. Finally, colorectal tumours and their adjacent normal tissues from 20 colorectal cancer patients were used to examine ASPP2 expression, p53 expression and p53 mutation, to understand their relationships with the patients' outcome. Three site mutations were found in p53 transcripts from 16 of 20 patients. ASPP2 mRNA expressions were higher, and autophagy level was lower in the adjacent normal tissues, compared with the tumour tissues, which was independent of both p53 mutation and expression level. Taken together, ASPP2 increased tumour sensitivity to chemotherapy via inhibiting autophagy in a p53-independent manner, which was associated with the tumour formation, suggesting that both p53 inactivation and ASPP2 expression level were involved in the sensitivity of colorectal cancer to chemotherapy.

SUBMITTER: Shi Y

PROVIDER: S-EPMC4369811 | biostudies-other | 2015 Mar

REPOSITORIES: biostudies-other

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ASPP2 enhances oxaliplatin (L-OHP)-induced colorectal cancer cell apoptosis in a p53-independent manner by inhibiting cell autophagy.

Shi Ying Y Han Yue Y Xie Fang F Wang Anna A Feng Xiaokun X Li Ning N Guo Hongliang H Chen Dexi D

Journal of cellular and molecular medicine 20141223 3

Inactivation of p53-mediated cell death pathways is a central component of cancer progression. ASPP2 (apoptosis stimulated protein of p53-2) is a p53 binding protein that specially stimulates pro-apoptosis function of p53. Down-regulation of ASPP2 is observed in many human cancers and is associated with poor prognosis and metastasis. In this study, ASPP2 was found to enhance L-OHP-induced apoptosis in HCT116 p53(-/-) cells in a p53-independent manner. Such apoptosis-promoting effect of ASPP2 was ...[more]

PMID: 25534115

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Project description:Colorectal carcinoma (CRC) is the most common cancer of the gastrointestinal tract with frequently dysregulated intracellular signaling pathways, including p53 signaling. The mainstay of chemotherapy treatment of CRC is 5-fluorouracil (5FU) and oxaliplatin. The two anticancer drugs mediate their therapeutic effect via DNA damage-triggered signaling. The small molecule reactivating p53 and inducing tumor apoptosis (RITA) is described as an activator of wild-type and reactivator of mutant p53 function, resulting in elevated levels of p53 protein, cell growth arrest, and cell death. Additionally, it has been shown that RITA can induce DNA damage signaling. It is expected that the therapeutic benefits of 5FU and oxaliplatin can be increased by enhancing DNA damage signaling pathways. Therefore, we highlighted the antiproliferative response of RITA alone and in combination with 5FU or oxaliplatin in human CRC cells. A panel of long-term established CRC cell lines (n=9) including p53 wild-type, p53 mutant, and p53 null and primary patient-derived, low-passage cell lines (n=5) with different p53 protein status were used for this study. A substantial number of CRC cells with pronounced sensitivity to RITA (IC50<3.0 μmol/l) were identified within established (4/9) and primary patient-derived (2/5) CRC cell lines harboring wild-type or mutant p53 protein. Sensitivity to RITA appeared independent of p53 status and was associated with an increase in antiproliferative response to 5FU and oxaliplatin, a transcriptional increase of p53 targets p21 and NOXA, and a decrease in MYC mRNA. The effect of RITA as an inducer of DNA damage was shown by a strong elevation of phosphorylated histone variant H2A.X, which was restricted to RITA-sensitive cells. Our data underline the primary effect of RITA, inducing DNA damage, and demonstrate the differential antiproliferative effect of RITA to CRC cells independent of p53 protein status. We found a substantial number of RITA-sensitive CRC cells within both panels of established CRC cell lines and primary patient-derived CRC cell lines (6/14) that provide a rationale for combining RITA with 5FU or oxaliplatin to enhance the antiproliferative response to both chemotherapeutic agents.

Dataset Information

ASPP2 enhances oxaliplatin (L-OHP)-induced colorectal cancer cell apoptosis in a p53-independent manner by inhibiting cell autophagy.

Publications

ASPP2 enhances oxaliplatin (L-OHP)-induced colorectal cancer cell apoptosis in a p53-independent manner by inhibiting cell autophagy.

Similar Datasets

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