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Global tumor protein p53/p63 interactome: making a case for cisplatin chemoresistance.

ABSTRACT: Cisplatin chemoresistance is a clinical problem that leads to treatment failure in various human epithelial cancers. Members of tumor protein (TP) p53 family play various critical roles in the multiple molecular mechanisms underlying the chemoresistance of tumor cells. However, the in-depth mechanisms of the cellular response to cisplatin-induced cell death are still under thorough investigation. We previously showed that squamous cell carcinoma (SCC) cells exposed to cisplatin display an ATM-dependent phosphorylation of ?Np63?, leading to a specific function of the phosphorylated (p)-?Np63? transcription factor in cisplatin-sensitive tumor cells. We further found that SCC cells expressing non-p-?Np63?-S385G became cisplatin-resistant. Using quantitative mass-spectrometry of protein complexes labeled with isobaric tags, we showed that TP53 and ?Np63? are involved in numerous protein-protein interactions, which are likely to be implicated in the response of tumor cells to cisplatin exposure. We found that p-?Np63? binds to the splicing complex, leading to repression of mRNA splicing and activation of ACIN1-mediated cell death pathway. In contrast to p-?Np63?, non-p-?Np63? fails to bind the critical members of the splicing complex, thereby leading to activation of RNA splicing and reduction of cell death pathway. Overall, our studies provide an integrated proteomic platform in making a case for the role of the p53/p63 interactome in cisplatin chemoresistance.

SUBMITTER: Huang Y

PROVIDER: S-EPMC3383596 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Global tumor protein p53/p63 interactome: making a case for cisplatin chemoresistance.

Huang Yiping Y Jeong Jun Seop JS Okamura Jun J Sook-Kim Myoung M Zhu Heng H Guerrero-Preston Rafael R Ratovitski Edward A EA

Cell cycle (Georgetown, Tex.) 20120615 12

Cisplatin chemoresistance is a clinical problem that leads to treatment failure in various human epithelial cancers. Members of tumor protein (TP) p53 family play various critical roles in the multiple molecular mechanisms underlying the chemoresistance of tumor cells. However, the in-depth mechanisms of the cellular response to cisplatin-induced cell death are still under thorough investigation. We previously showed that squamous cell carcinoma (SCC) cells exposed to cisplatin display an ATM-de ...[more]

PMID: 22672905

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Project description:Perfluorocarbon nanoparticles have been reported to deliver oxygen to tumors and reduce hypoxia-induced radioresistance, however few studies have been carried out to study its role in reducing hypoxia-induced chemoresistance. The oxygenation effect also varies dramatically between different perfluorocarbon formulations and protocols, and there have been no efficient tools to monitor dynamic changes of tumor oxygenation non-invasively. Our goal was to promote tumor oxygenation using perfluorooctyl bromide (PFOB) nanoemulsion and to assess its role in sensitizing tumors to cisplatin treatment. A novel optical imaging protocol was also created to monitor the dynamic changes of tumor oxygenation in real-time. Methods: PFOB nanoemulsion with high oxygen-carrying capacity was prepared and administered to tumor-bearing mice intravenously. Tumor oxygenation was monitored using optical imaging with a hypoxia probe injected intratumorally, thus the oxygenation dynamics and best oxygenation protocol were determined. Various treatment groups were studied, and the tumor growth was monitored to evaluate the role of oxygenation in sensitizing tumors to cisplatin treatment. Results: PFOB nanoemulsion with and without pre-oxygenation along with carbogen breathing resulted in much better tumor oxygenation compared to carbogen breathing alone, while PFOB with air breathing did not show significant increase in tumor oxygenation. Pre-oxygenated PFOB with carbogen breathing produced the most effective oxygenation as early as 5 min post administration. In vitro and in vivo data showed preoxygenated PFOB nanoemulsion with carbogen breathing could increase cisplatin-mediated apoptosis of cancer cells and inhibited tumor growth at a low dose of cisplatin (1 mg/kg) treatment. Furthermore, the treatment did not induce nephrotoxicity. Conclusions: Preoxygenated PFOB nanoemulsion with carbogen breathing can effectively increase tumor oxygenation, which has a great potential to prevent/overcome hypoxia-induced chemotherapy resistance. In addition, optical imaging with intratumoral injection of the hypoxia probe was an efficient tool to monitor tumor oxygenation dynamics during PFOB administration, providing better understanding on oxygenation effects under different protocols.

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Global tumor protein p53/p63 interactome: making a case for cisplatin chemoresistance.

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Global tumor protein p53/p63 interactome: making a case for cisplatin chemoresistance.

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