The Antitumor Agent PBT-1 Directly Targets HSP90 and hnRNP A2/B1 and Inhibits Lung Adenocarcinoma Growth and Metastasis

Chen, Chi Yuan; Yang, Shuenn Chen; Lee, Kuo Hsiung̀; Yang, Xiaoming; Lin, Wei; Chow, Lu-Ping; Wang, Tzu-Chien V.; Hong, Tse-Ming; Lin, Jau Chen; Crysline, Kuan,; Yang, Pan Chyr

doi:10.1021/jm401686b

Cited by 23 publications

(17 citation statements)

References 28 publications

(64 reference statements)

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“…Compounds that block hnRNP interactions are currently underexplored but are not unprecedented. For example, the anti-tumor natural product camptothecin was found to inhibit hnRNP A1-topoisomerase 1 interactions (Manita et al 2011), while a synthetic phenanthrene-based tylophorine derivative was determined to bind to hnRNP A2/ B1 and reduce lung adenocarcinoma growth and metastasis (Chen et al 2014). Thus, understanding the molecular mechanisms of hnRNPs cellular functions may help identify new therapeutic strategies to combat cancers and neurodegenerative diseases.…”

Section: Introductionmentioning

confidence: 99%

HNRNPH1-dependent splicing of a fusion oncogene reveals a targetable RNA G-quadruplex interaction

Neckles

Boer

Aboreden

et al. 2019

RNA

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The primary oncogenic event in ∼85% of Ewing sarcomas is a chromosomal translocation that generates a fusion oncogene encoding an aberrant transcription factor. The exact genomic breakpoints within the translocated genes, EWSR1 and FLI1, vary; however, in EWSR1, breakpoints typically occur within introns 7 or 8. We previously found that in Ewing sarcoma cells harboring EWSR1 intron 8 breakpoints, the RNA-binding protein HNRNPH1 facilitates a splicing event that excludes EWSR1 exon 8 from the EWS-FLI1 pre-mRNA to generate an in-frame mRNA. Here, we show that the processing of distinct EWS-FLI1 pre-mRNAs by HNRNPH1, but not other homologous family members, resembles alternative splicing of transcript variants of EWSR1. We demonstrate that HNRNPH1 recruitment is driven by guanine-rich sequences within EWSR1 exon 8 that have the potential to fold into RNA G-quadruplex structures. Critically, we demonstrate that an RNA mimetic of one of these G-quadruplexes modulates HNRNPH1 binding and induces a decrease in the growth of an EWSR1 exon 8 fusion-positive Ewing sarcoma cell line. Finally, we show that EWSR1 exon 8 fusion-positive cell lines are more sensitive to treatment with the pan-quadruplex binding molecule, pyridostatin (PDS), than EWSR1 exon 8 fusion-negative lines. Also, the treatment of EWSR1 exon 8 fusion-positive cells with PDS decreases EWS-FLI1 transcriptional activity, reversing the transcriptional deregulation driven by EWS-FLI1. Our findings illustrate that modulation of the alternative splicing of EWS-FLI1 pre-mRNA is a novel strategy for future therapeutics against the EWSR1 exon 8 containing fusion oncogenes present in a third of Ewing sarcoma.

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Section: Introductionmentioning

confidence: 99%

HNRNPH1-dependent splicing of a fusion oncogene reveals a targetable RNA G-quadruplex interaction

Neckles

Boer

Aboreden

et al. 2019

RNA

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“…A recent study showed that phenanthrene-based tylophorine-1 (PBT-1) binds to hnRNPA2B1 and exerts antitumor activity in part by reducing AKT-mediated lung adenocarcinoma metastasis and tumorigenesis ( Chen et al, 2014 ). The suppression of hnRNPA2B1 was associated with increased p21 and growth inhibition in HaCaT and Colo16 cells ( He et al, 2005 ).…”

Section: Discussionmentioning

confidence: 99%

LncRNA-uc002mbe.2 Interacting with hnRNPA2B1 Mediates AKT Deactivation and p21 Up-Regulation Induced by Trichostatin in Liver Cancer Cells

Chen

Xue

et al. 2017

Front. Pharmacol.

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Long non-coding RNAs (lncRNAs) have been implicated in liver carcinogenesis. We previously showed that the induction of lncRNA-uc002mbe.2 is positively associated with the apoptotic effect of trichostatin A (TSA) in hepatocellular carcinoma (HCC) cells. The current study further analyzed the role of uc002mbe.2 in TSA-induced liver cancer cell death. The level of uc002mbe.2 was markedly increased by TSA in the cytoplasm of HCC cells. Knockdown of uc002mbe.2 prohibited TSA-induced G2/M cell cycle arrest, p21 induction, and apoptosis of Huh7 cells and reversed the TSA-mediated decrease in p-AKT. RNA pull-down and RNA-binding protein immunoprecipitation (RIP) assays revealed that TSA induced an interaction between uc002mbe.2 and heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) in Huh7 cells. This interaction mediated AKT deactivation and p21 induction in liver cancer cells. In an athymic xenograft mouse model, knockdown of uc002mbe.2 significantly prohibited the TSA-mediated reduction in tumor size and weight. In addition, the ability of TSA to reduce hnRNPA2B1 and p-AKT levels and induce p21 in the xenograft tumors was prevented by uc002mbe.2 knockdown. Therefore, the interaction of uc002mbe.2 and hnRNPA2B1 in mediating AKT deactivation and p21 induction is involved in the cytostatic effect of trichostatin in liver cancer cells.

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“…Tumors were generally palpable at 5 days after inoculation. Drug treatment began at Day 5 and tumor volumes were measured (using a caliper and calculated as length x width 2 × 0.5) twice weekly until 21 days after injection [ 21 ]. All animal experiments were performed in accordance with the guidelines for the Animal Care Ethics Commission of Chang Gung University under an approved animal protocol.…”

Section: Methodsmentioning

confidence: 99%

Sulforaphane attenuates EGFR signaling in NSCLC cells

Chen

Chuang

et al. 2015

J Biomed Sci

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BackgroundEGFR, a receptor tyrosine kinase (RTK), is frequently overexpressed and mutated in non-small cell lung cancer (NSCLC). Tyrosine kinase inhibitors (TKIs) have been widely used in the treatment of many cancers, including NSCLC. However, intrinsic and acquired resistance to TKI remains a common obstacle. One strategy that may help overcome EGFR-TKI resistance is to target EGFR for degradation. As EGFR is a client protein of heat-shock protein 90 (HSP90) and sulforaphane is known to functionally regulate HSP90, we hypothesized that sulforaphane could attenuate EGFR-related signaling and potentially be used to treat NSCLC.ResultsOur study revealed that sulforaphane displayed antitumor activity against NSCLC cells both in vitro and in vivo. The sensitivity of NSCLC cells to sulforaphane appeared to positively correlate with the inhibition of EGFR-related signaling, which was attributed to the increased proteasomal degradation of EGFR. Combined treatment of NSCLC cells with sulforaphane plus another HSP90 inhibitor (17-AAG) enhanced the inhibition of EGFR-related signaling both in vitro and in vivo.ConclusionsWe have shown that sulforaphane is a novel inhibitory modulator of EGFR expression and is effective in inhibiting the tumor growth of EGFR-TKI-resistant NSCLC cells. Our findings suggest that sulforaphane should be further explored for its potential clinical applications against NSCLC.

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The Antitumor Agent PBT-1 Directly Targets HSP90 and hnRNP A2/B1 and Inhibits Lung Adenocarcinoma Growth and Metastasis

Cited by 23 publications

References 28 publications

HNRNPH1-dependent splicing of a fusion oncogene reveals a targetable RNA G-quadruplex interaction

HNRNPH1-dependent splicing of a fusion oncogene reveals a targetable RNA G-quadruplex interaction

LncRNA-uc002mbe.2 Interacting with hnRNPA2B1 Mediates AKT Deactivation and p21 Up-Regulation Induced by Trichostatin in Liver Cancer Cells

Sulforaphane attenuates EGFR signaling in NSCLC cells

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