NAC1 Modulates Sensitivity of Ovarian Cancer Cells to Cisplatin via Altering the HMGB1-Mediated Autophagic Response

Department of Pharmacology, Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine and Milton S. Hershey Medical Center, Hershey, PA, USA.
Oncogene (Impact Factor: 8.46). 07/2011; 31(8):1055-64. DOI: 10.1038/onc.2011.290
Source: PubMed

ABSTRACT Nucleus accumbens-1 (NAC1), a nuclear factor belonging to the BTB/POZ gene family, is known to have important roles in proliferation and growth of tumor cells and in chemotherapy resistance. Yet, the mechanisms underlying how NAC1 contributes to drug resistance remain largely unclear. We report here that autophagy was involved in NAC1-mediated resistance to cisplatin, a commonly used chemotherapeutic drug in the treatment of ovarian cancer. We found that treatment with cisplatin caused an activation of autophagy in ovarian cancer cell lines, A2780, OVCAR3 and SKOV3. We further demonstrated that knockdown of NAC1 by RNA interference or inactivation of NAC1 by inducing the expression of a NAC1 deletion mutant that contains only the BTB/POZ domain significantly inhibited the cisplatin-induced autophagy, resulting in increased cisplatin cytotoxicity. Moreover, inhibition of autophagy and sensitization to cisplatin by NAC1 knockdown or inactivation were accompanied by induction of apoptosis. To confirm that the sensitizing effect of NAC1 inhibition on the cytotoxicity of cisplatin was attributed to suppression of autophagy, we assessed the effects of the autophagy inhibitors 3-methyladenosine and chloroquine, and small interfering RNAs (siRNAs) targeting beclin 1 or Atg5 on the cytotoxicity of cisplatin. Treatment with 3-methyladenosine, chloroquine or beclin 1 and Atg5-targeted siRNA also enhanced the sensitivity of SKOV3, A2780 and OVCAR3 cells to cisplatin, indicating that suppression of autophagy indeed renders tumor cells more sensitive to cisplatin. Regulation of autophagy by NAC1 was mediated by the high-mobility group box 1 (HMGB1), as the functional status of NAC1 was associated with the expression, translocation and release of HMGB1. The results of our study not only revealed a new mechanism determining cisplatin sensitivity but also identified NAC1 as a novel regulator of autophagy. Thus, the NAC1-mediated autophagy may be exploited as a new target for enhancing the efficacy of cisplatin against ovarian cancer and other types of malignancies.

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Available from: Kai Lee Yap, Sep 27, 2015
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    • "These were NACC1, mapped to Chromosome 19p13.2, known to alter the HMGB1-mediated autophagic response (23) and carrying seven predicted binding sites for miR-608; the Chromosome 11p15 TPP1 tripeptidyl-peptidase 1 lipid metabolism-regulating enzyme (24), with two predicted sites for miR-608; and the Chromosome 11p13 validated angiogenesis regulating target CD44 (19), with one binding site for miR-608. Enhanced suppression of each of these putative target genes in cells carrying the A-allele compared with the C-allele (Fig. 3D) demonstrated that this effect extends beyond CDC42 and IL6 differences and that it occurs in transcripts of different chromosomal origins carrying different numbers of miR-608-binding sites. "
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    Human Molecular Genetics 04/2014; 23(17). DOI:10.1093/hmg/ddu170 · 6.39 Impact Factor
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    • "3.3. The miR-30d mimic can sensitize ATC cells to cisplatin We previous demonstrated that the cisplatin-induced autophagy was cyto-protective in ovarian cancer and some other types of cancer cells [17]. Here, we sought to understand how autophagy activated by cisplatin affects the survival of ATC cells and how suppression of the cisplatin-activated Fig. 5. MiR-30d mimic increases sensitivity of ATC cells to cisplatin. "
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    ABSTRACT: miR-30d has been observed to be significantly down-regulated in human anaplastic thyroid carcinoma (ATC), and is believed to be an important event in thyroid cell transformation. In this study, we found that miR-30d has a critical role in modulating sensitivity of ATC cells to cisplatin, a commonly used chemotherapeutic drug for treatment of this neoplasm. Using a mimic of miR-30d, we demonstrated that miR-30d could negatively regulate the expression of beclin 1, a key autophagy gene, leading to suppression of the cisplatin-activated autophagic response that protects ATC cells from apoptosis. A reporter gene assay demonstrated that the binding sequences of miR-30d in the beclin 1-3' UTR was the region required for the inhibition of beclin 1 expression by this miRNA. We further showed that inhibition of the beclin 1-mediated autophagy by the miR-30d mimic sensitized ATC cells to cisplatin both in vitro (cell culture) and in vivo (animal xenograft model). These results suggest that dysregulation of miR-30d in ATC cells is responsible for the insensitivity to cisplatin by promoting autophagic survival. Thus, miR-30d may be exploited as a potential target for therapeutic intervention in the treatment of ATC.
    Biochemical pharmacology 12/2013; 87(4). DOI:10.1016/j.bcp.2013.12.004 · 5.01 Impact Factor
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    • "The treatment of HT1376, T24, and 5637 urinary bladder-cancer cell lines with cisplatin and sunitinib malate, in isolation, significantly (P < 0.05) reduced cell viability in a dose-dependent manner as already reported in our previous studies [7, 20]. Similar results were described on 5637, J82, HT1197, and 253J urinary bladder-cancer cell lines [21], as well as on A2780 and OVCAR3 ovarian cancer cells [22] when exposed to cisplatin in isolation. Concerning sunitinib malate, its effect was already reported on 5637 [23], TCC-SUP, HTB5, HTB9, T24, UMUC14, SW1710, and J82 urinary bladder-cancer cell lines [24]. "
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    11/2013; 2013(2):791406. DOI:10.1155/2013/791406
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