Lu WJ, Lee NP, Kaul SC, Lan F, Poon RT, Wadhwa R et al.. Induction of mutant p53-dependent apoptosis in human hepatocellular carcinoma by targeting stress protein mortalin. Int J Cancer 129: 1806-1814

Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China.
International Journal of Cancer (Impact Factor: 5.09). 10/2011; 129(8):1806-14. DOI: 10.1002/ijc.25857
Source: PubMed


Stress protein mortalin (mtHSP70) is highly expressed in cancer cells. It was shown to contribute to carcinogenesis by sequestrating the wild type p53, a key tumor suppressor protein, in the cytoplasm resulting in an abrogation of its transcriptional activation function. We have found that the level of mortalin expression has significant correlation with human hepatocellular carcinoma (HCC) malignancy and therefore investigated whether it interacts with and influences the activities of mutant p53, frequently associated with HCC development. We have detected mortalin-p53 interactions in liver tumor and five HCC cell lines that harbored mutant p53. The data was in contrast to the normal liver and immortalized normal hepatocytes that lacked mortalin-p53 interaction. Furthermore, we have found that the shRNA-mediated mortalin silencing could induce mutant p53-mediated tumor-specific apoptosis in HCC. Such allotment of apoptotic function to mutant p53 by targeting mortalin-p53 interaction in cancer cells is a promising strategy for HCC therapy.

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Available from: Wen jing Lu, Jul 16, 2014
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    • "Mortalin has also been detected in the serum of colorectal patients, suggesting it as a general cancer diagnostic marker (Rozenberg et al. 2011). In our earlier studies, we reported an upregulation of mortalin in a large variety of cancer cells and clinical samples of HCC (Dundas et al. 2005; Lu et al. 2011a, b; Yi et al. 2008; Klaus et al. 2014; Sane et al. 2014). Based on these data, we hypothesized that circulating mortalin and mortalin autoantibody might be elevated in serum of HCC patients. "
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    ABSTRACT: Mortalin is a stress chaperone belonging to the Hsp70 family of proteins. Frequently enriched in cancers, it is a multifunctional protein and regulates cell proliferation, apoptosis, mitochondrial functions, and the activity of tumor suppressor protein p53. In the present study, we investigated circulating mortalin and its autoantibody in normal, cirrhosis, and cancerous liver. We found that although mortalin is enriched in liver cancer cells and tumors, it is not detected in the serum of either the liver cirrhosis or cancer patients. In contrast, mortalin autoantibody was detected in patients' sera and showed significant correlation with the occurrence of cirrhosis. It is suggested as a potential noninvasive marker for liver cirrhosis.
    Full-text · Article · Apr 2015 · Cell Stress and Chaperones
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    • "High prevalence of p53 alterations have been investigated in HCC as a consequence of chronic hepatitis B.9,10 HBV encodes a small protein x (HBx) that seems to play a critical role in hepatocarcinogenesis and found to be expressed in chronic hepatitis, cirrhotic liver, and hepatocellular carcinoma (HCC).11,12 However, preliminary reports verify that the distal C-terminal region of HBx has inhibitory effect on apoptosis through inactivation of p53 in microinjected human fibroblasts.13,14 "
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    ABSTRACT: Background: The ability of tumour suppressor protein p53 (P53) to regulate cell cycle processes can be modulated by hepatitis B virus (HBV). While preliminary evidences indicates the involvement of protein-x of HBV (HBx) in altering p53 DNA binding, no further data have been accumulated for the significance of serum p53 in chronic hepatitis B virus infected patients. Methods: 72 non-cirrhotic and 19 cirrhotic patients infected by HBV were enrolled for the analysis in this study. Enzyme linked immunosorbent assay (ELISA) was performed to study the concentrations of serum p53 protein. The tertiary structures of HBx and P53 were docked by Z-dock and Hex servers for in-silico protein-protein interaction analysis. Results: There was a significant association between the serum p53 and cirrhosis (OR=1.81 95% CI: 1.017-3.2, P=0.044). Cirrhotic patients had higher level of serum p53 compare with chronic infection of HBV (1.98±1.22 vs. 1.29±0.72 U/ml, P=0.05). No evidence of correlation was seen between the different variables such as age, gender, log viral load, serum alkaline phosphatase (ALP) and alanine aminotransferase (ALT) with serum p53. Tertiary model shows that the amino acid residues from Arg110 to Lys132 of the N-terminal of P53 which is critical for ubiquitination, are bonded to a region in N- terminal of HBx amino acid residues from Arg19 to Ser33. Conclusion: There is an increase in serum p53 in HBV-related cirrhosis patients. In this case, HBx might be responsible for such higher concentration of p53 through HBx-p53 protein-protein interaction, as is shown by molecular modeling approach.
    Full-text · Article · Sep 2014 · Iranian Journal of Medical Sciences
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    • "Although, mutation in p53 is frequently found in liver tumors, the major of p53 mutation observed in HCC is at the third position of codon 249 resulting in a G:C to T: A transversion [45]–[48]. Lu et. have evidenced that the inhibition of GRP75 can still strongly reactivate the apoptotic function of mutant p53 in HCC cells [49]. Thus, such therapeutic strategy that dual targeting of GRP75 and HSP90 will be excepted to be effective in part HCC which harboring mutant p53. "
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    ABSTRACT: Heat shock protein 90 (HSP90) inhibitors are potential drugs for cancer therapy. The inhibition of HSP90 on cancer cell growth largely through degrading client proteins, like Akt and p53, therefore, triggering cancer cell apoptosis. Here, we show that the HSP90 inhibitor 17-AAG can induce the expression of GRP75, a member of heat shock protein 70 (HSP70) family, which, in turn, attenuates the anti-growth effect of HSP90 inhibition on cancer cells. Additionally, 17-AAG enhanced binding of GRP75 and p53, resulting in the retention of p53 in the cytoplasm. Blocking GRP75 with its inhibitor MKT-077 potentiated the anti-tumor effects of 17-AAG by disrupting the formation of GRP75-p53 complexes, thereby facilitating translocation of p53 into the nuclei and leading to the induction of apoptosis-related genes. Finally, dual inhibition of HSP90 and GRP75 was found to significantly inhibit tumor growth in a liver cancer xenograft model. In conclusion, the GRP75 inhibitor MKT-077 enhances 17-AAG-induced apoptosis in HCCs and increases p53-mediated inhibition of tumor growth in vivo. Dual targeting of GRP75 and HSP90 may be a useful strategy for the treatment of HCCs.
    Full-text · Article · Jan 2014 · PLoS ONE
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