Chemical Proteomics Identifies Heterogeneous Nuclear Ribonucleoprotein (hnRNP) A1 as the Molecular Target of Quercetin in Its Anti-cancer Effects in PC-3 Cells

Ko, Chia-Chen; Chen, Yun‐Ju; Chen, Chih-Ta; Liu, Yu-Chih; Cheng, Fang; Hsu, Kai-Chao; Chow, Lu-Ping

doi:10.1074/jbc.m114.553248

Cited by 50 publications

(36 citation statements)

References 33 publications

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“…Hence, we hypothesized that downregulation of hnRNPA1 expression may assist in suppressing the expression of AR-V7, and consequently in prolonging the effectiveness of enzalutamide. A recent report (25) disclosed that quercetin, a phytoflavonoid, exerts its anti-cancer effects by binding to and impairing the ability of hnRNPA1 to shuttle between the nucleus and cytoplasm, resulting in its cytoplasmic retention. Hence, we analyzed whether quercetin affects the expression of hnRNPA1.…”

Section: Resultsmentioning

confidence: 99%

“…In view of these findings, efforts are underway to identify or develop novel molecules that can antagonize either the expression or activity of hnRNPA1. We analyzed published literature to identify potential candidates and found a report of an interaction between quercetin and hnRNPA1 (25). The study found that quercetin binds to and retains hnRNPA1 in the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

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Quercetin Targets hnRNPA1 to Overcome Enzalutamide Resistance in Prostate Cancer Cells

Tummala

Lou

Gao

et al. 2017

Molecular Cancer Therapeutics

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Prostate cancer remains dependent on androgen receptor signaling even after castration. Aberrant androgen receptor signaling in castration resistant prostate cancer is mediated by mechanisms such as alterations in the androgen receptor and activation of interacting signaling pathways. Clinical evidence confirms that resistance to the next generation anti-androgen, enzalutamide, may be mediated to a large extent by alternative splicing of the androgen receptor to generate constitutively active splice variants such as AR-V7. The splice variants AR-V7 and Arv567es have been implicated in the resistance to not only enzalutamide, but also to abiraterone and other conventional therapeutics such as taxanes. Numerous studies including ours suggest that splicing factors such as hnRNPA1 promote the generation of AR-V7, thus contributing to enzalutamide resistance in prostate cancer cells. In the present study, we discovered that quercetin, a naturally occurring polyphenolic compound, reduces the expression of hnRNPA1, and consequently, that of AR-V7. The suppression of AR-V7 by quercetin resensitizes enzalutamide-resistant prostate cancer cells to treatment with enzalutamide. Our results indicate that quercetin downregulates hnRNPA1 expression, downregulates the expression of AR-V7, antagonizes androgen receptor signaling, and resensitizes enzalutamide-resistant prostate cancer cells to enzalutamide treatment in vivo in mouse xenografts. These findings demonstrate that suppressing the alternative splicing of the androgen receptor may have important implications in overcoming the resistance to next-generation anti-androgen therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Quercetin Targets hnRNPA1 to Overcome Enzalutamide Resistance in Prostate Cancer Cells

Tummala

Lou

Gao

et al. 2017

Molecular Cancer Therapeutics

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“…The plant flavonoid quercetin has been demonstrated to inhibit prostate cancer growth and, more recently, to target hnRNP A1 (37). Quercetin was shown to bind the F peptide region of hnRNP A1, impairing its ability to shuttle between the nucleus and cytoplasm, resulting in cytoplasmic retention.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Target of Rapamycin (mTOR) Inhibition Synergizes with Reduced Internal Ribosome Entry Site (IRES)-mediated Translation of Cyclin D1 and c-MYC mRNAs to Treat Glioblastoma

Holmes

Lee

Landon

et al. 2016

Journal of Biological Chemistry

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Our previous work has demonstrated an intrinsic mRNAspecific protein synthesis salvage pathway operative in glioblastoma (GBM) tumor cells that is resistant to mechanistic target of rapamycin (mTOR) inhibitors. The activation of this internal ribosome entry site (IRES)-dependent mRNA translation initiation pathway results in continued translation of critical transcripts involved in cell cycle progression in the face of global eIF-4E-mediated translation inhibition. Recently we identified compound 11 (C11), a small molecule capable of inhibiting c-MYC IRES translation as a consequence of blocking the interaction of a requisite c-MYC IRES trans-acting factor, heterogeneous nuclear ribonucleoprotein A1, with its IRES. Here we demonstrate that C11 also blocks cyclin D1 IRES-dependent initiation and demonstrates synergistic anti-GBM properties when combined with the mechanistic target of rapamycin kinase inhibitor PP242. The structure-activity relationship of C11 was investigated and resulted in the identification of IRES-J007, which displayed improved IRES-dependent initiation blockade and synergistic anti-GBM effects with PP242. Mechanistic studies with C11 and IRES-J007 revealed binding of the inhibitors within the UP1 fragment of heterogeneous nuclear ribonucleoprotein A1, and docking analysis suggested a small pocket within close proximity to RRM2 as the potential binding site. We further demonstrate that co-therapy with IRES-J007 and PP242 significantly reduces tumor growth of GBM xenografts in mice and that combined inhibitor treatments markedly reduce the mRNA translational state of cyclin D1 and c-MYC transcripts in these tumors. These data support the combined use of IRES-J007 and PP242 to achieve synergistic antitumor responses in GBM.

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“…Another plant metabolite, quercetin, has also been found to directly bind to the C-terminal region of hnRNPA1 [60]. However, as compared to the shikonin treatment shown in this study, quercetin treatment was reported to result in a different suppression activity in hnRNPA1-mediated posttranscriptional processes.…”

Section: Discussionmentioning

confidence: 59%

“…However, as compared to the shikonin treatment shown in this study, quercetin treatment was reported to result in a different suppression activity in hnRNPA1-mediated posttranscriptional processes. Quercetin treatment at 100 μM for 18 h, only suppressed the translocation of hnRNPA1 from the cytoplasm back into the nucleus, hence causing accumulation of hnRNPA1 in the cytoplasm [60]. In comparison, SK treatment at 1 μM for 2 h was found in this study to disrupt the hnRNPA1-mediated nuclear export activity of the newly synthesized RNA into the cytosol.…”

Section: Discussionmentioning

confidence: 70%

Immunogenicity of mammary tumor cells can be induced by shikonin via direct binding-interference with hnRNPA1

et al. 2016

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Immunogenic cell death (ICD) of tumor cells occurs via various pathways that activate immune cell systems against cancer. Previous studies have demonstrated that shikonin (SK), a plant secondary metabolite, can confer strong pharmacological activities that activate ICD and strong immunogenicity of tumor cells. However, the exact hierarchical regulatory mechanisms including the molecular targets of SK-activated immunogenicity are still unknown. Here, the heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) was revealed to serve as a specific protein target for SK. This binding plays a key role in SK-stimulated ICD activity and the suppression of post-transcriptional mRNA processing, including nuclear export activity of newly synthesized mRNAs in mammary carcinoma cells in vitro. Moreover, it also mechanistically mediates the anti-metastatic effect of a tumor cell lysate (TCL) vaccine, which can be readily generated from SK-treated 4T1 tumor cells (SK-TCL), and the derived tumor-immunogenicity of SK-TCL-treated dendritic cells in vivo. Together, the identification of hnRNPA1 as the intracellular molecular target provides compelling pharmacology-based knowledge for the potential clinical use of SK-induced immunogenicity. In addition, SK may also serve as a potent suppressor that interferes with specific post-transcriptional activities, a mechanism which may be useful for exploitation in cancer therapeutics.

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Chemical Proteomics Identifies Heterogeneous Nuclear Ribonucleoprotein (hnRNP) A1 as the Molecular Target of Quercetin in Its Anti-cancer Effects in PC-3 Cells

Cited by 50 publications

References 33 publications

Quercetin Targets hnRNPA1 to Overcome Enzalutamide Resistance in Prostate Cancer Cells

Quercetin Targets hnRNPA1 to Overcome Enzalutamide Resistance in Prostate Cancer Cells

Mechanistic Target of Rapamycin (mTOR) Inhibition Synergizes with Reduced Internal Ribosome Entry Site (IRES)-mediated Translation of Cyclin D1 and c-MYC mRNAs to Treat Glioblastoma

Immunogenicity of mammary tumor cells can be induced by shikonin via direct binding-interference with hnRNPA1

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