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Open AccessArticle

Haprolid Inhibits Tumor Growth of Hepatocellular Carcinoma through Rb/E2F and Akt/mTOR Inhibition

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Department of Internal Medicine I, Medical University Hospital, Eberhard Karls Universität Tübingen, 72076 Tubingen, Germany
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The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
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Department of Internal Medicine VIII, Medical University Hospital, 72076 Tübingen, Germany
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Department Microbial Drugs, Helmholtz Centre for Infection Research GmbH (HZI), 38124 Braunschweig, Germany
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Institute of Pathology, Hannover Regional Hospital, 30043 Hannover, Germany
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Institute of Organic Chemistry, Leibniz University of Hannover, 30167 Hannover, Germany
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Centre of Biomolecular Drug Research, Helmholtz Centre for Infection Research GmbH (HZI), 38124 Braunschweig, Germany
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Department of Internal Medicine II, Klinikum Bremen Nord, 28755 Bremen, Germany
*
Authors to whom correspondence should be addressed.
Cancers 2020, 12(3), 615; https://doi.org/10.3390/cancers12030615
Received: 1 December 2019 / Revised: 4 February 2020 / Accepted: 5 February 2020 / Published: 6 March 2020
Background: Hepatocellular carcinoma (HCC) represents a major health burden with limited curative treatment options. There is a substantial unmet need to develop innovative approaches to impact the progression of advanced HCC. Haprolid is a novel natural component isolated from myxobacteria. Haprolid has been reported as a potent selective cytotoxin against a panel of tumor cells in recent studies including HCC cells. The aims of this study are to evaluate the antitumor effect of haprolid in HCC and to understand its underlying molecular mechanisms. Methods: The efficacy of haprolid was evaluated in human HCC cell lines (Huh-7, Hep3B and HepG2) and xenograft tumors (NMRI-Foxn1nu mice with injection of Hep3B cells). Cytotoxic activity of haprolid was determined by the WST-1 and crystal violet assay. Wound healing, transwell and tumorsphere assays were performed to investigate migration and invasion of HCC cells. Apoptosis and cell-cycle distribution were measured by flow cytometry. The effects of haprolid on the Rb/E2F and Akt/mTOR pathway were examined by immunoblotting and immunohistochemistry. Results: haprolid treatment significantly inhibited cell proliferation, migration and invasion in vitro. The epithelial–mesenchymal transition (EMT) was impaired by haprolid treatment and the expression level of N-cadherin, vimentin and Snail was downregulated. Moreover, growth of HCC cells in vitro was suppressed by inhibition of G1/S transition, and partially by induction of apoptosis. The drug induced downregulation of cell cycle regulatory proteins cyclin A, cyclin B and CDK2 and induced upregulation of p21 and p27. Further evidence showed that these effects of haprolid were associated with Rb/E2F downregulation and Akt/mTOR inhibition. Finally, in vivo nude mice experiments demonstrated significant inhibition of tumor growth upon haprolid treatment. Conclusion: Our results show that haprolid inhibits the growth of HCC through dual inhibition of Rb/E2F and Akt/mTOR pathways. Therefore, haprolid might be considered as a new and promising candidate for the palliative therapy of HCC. View Full-Text
Keywords: HCC; haprolid; Rb/E2F; Akt/mTOR; EMT; cell cycle; apoptosis HCC; haprolid; Rb/E2F; Akt/mTOR; EMT; cell cycle; apoptosis
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Xing, J.; Bhuria, V.; Bui, K.C.; Nguyen, M.L.T.; Hu, Z.; Hsieh, C.-J.; Wittstein, K.; Stadler, M.; Wilkens, L.; Li, J.; Kalesse, M.; Bozko, P.; Plentz, R.R. Haprolid Inhibits Tumor Growth of Hepatocellular Carcinoma through Rb/E2F and Akt/mTOR Inhibition. Cancers 2020, 12, 615.

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