Haprolid Inhibits Tumor Growth of Hepatocellular Carcinoma through Rb/E2F and Akt/mTOR Inhibition
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. Haproli...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-03-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/12/3/615 |
| _version_ | 1797717559605198848 |
|---|---|
| author | Jun Xing Vikas Bhuria Khac Cuong Bui Mai Ly Thi Nguyen Zexi Hu Chih-Jen Hsieh Kathrin Wittstein Marc Stadler Ludwig Wilkens Jun Li Markus Kalesse Przemyslaw Bozko Ruben R. Plentz |
| author_facet | Jun Xing Vikas Bhuria Khac Cuong Bui Mai Ly Thi Nguyen Zexi Hu Chih-Jen Hsieh Kathrin Wittstein Marc Stadler Ludwig Wilkens Jun Li Markus Kalesse Przemyslaw Bozko Ruben R. Plentz |
| author_sort | Jun Xing |
| collection | DOAJ |
| description | 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-Foxn1<sup>nu</sup> 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<i> </i>through dual inhibition of Rb/E2F and Akt/mTOR pathways<i>.</i> Therefore, haprolid might be considered as a new and promising candidate for the palliative therapy of HCC. |
| first_indexed | 2024-03-12T08:38:05Z |
| format | Article |
| id | doaj.art-b0c1fa0fe4f44638aa322e3a43b7c202 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T08:38:05Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-b0c1fa0fe4f44638aa322e3a43b7c2022023-09-02T17:06:53ZengMDPI AGCancers2072-66942020-03-0112361510.3390/cancers12030615cancers12030615Haprolid Inhibits Tumor Growth of Hepatocellular Carcinoma through Rb/E2F and Akt/mTOR InhibitionJun Xing0Vikas Bhuria1Khac Cuong Bui2Mai Ly Thi Nguyen3Zexi Hu4Chih-Jen Hsieh5Kathrin Wittstein6Marc Stadler7Ludwig Wilkens8Jun Li9Markus Kalesse10Przemyslaw Bozko11Ruben R. Plentz12Department of Internal Medicine I, Medical University Hospital, Eberhard Karls Universität Tübingen, 72076 Tubingen, GermanyDepartment of Internal Medicine I, Medical University Hospital, Eberhard Karls Universität Tübingen, 72076 Tubingen, GermanyDepartment of Internal Medicine I, Medical University Hospital, Eberhard Karls Universität Tübingen, 72076 Tubingen, GermanyDepartment of Internal Medicine I, Medical University Hospital, Eberhard Karls Universität Tübingen, 72076 Tubingen, GermanyDepartment of Internal Medicine VIII, Medical University Hospital, 72076 Tübingen, GermanyDepartment of Internal Medicine I, Medical University Hospital, Eberhard Karls Universität Tübingen, 72076 Tubingen, GermanyDepartment Microbial Drugs, Helmholtz Centre for Infection Research GmbH (HZI), 38124 Braunschweig, GermanyDepartment Microbial Drugs, Helmholtz Centre for Infection Research GmbH (HZI), 38124 Braunschweig, GermanyInstitute of Pathology, Hannover Regional Hospital, 30043 Hannover, GermanyInstitute of Organic Chemistry, Leibniz University of Hannover, 30167 Hannover, GermanyInstitute of Organic Chemistry, Leibniz University of Hannover, 30167 Hannover, GermanyDepartment of Internal Medicine I, Medical University Hospital, Eberhard Karls Universität Tübingen, 72076 Tubingen, GermanyDepartment of Internal Medicine I, Medical University Hospital, Eberhard Karls Universität Tübingen, 72076 Tubingen, GermanyBackground: 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-Foxn1<sup>nu</sup> 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<i> </i>through dual inhibition of Rb/E2F and Akt/mTOR pathways<i>.</i> Therefore, haprolid might be considered as a new and promising candidate for the palliative therapy of HCC.https://www.mdpi.com/2072-6694/12/3/615hcchaprolidrb/e2fakt/mtoremtcell cycleapoptosis |
| spellingShingle | Jun Xing Vikas Bhuria Khac Cuong Bui Mai Ly Thi Nguyen Zexi Hu Chih-Jen Hsieh Kathrin Wittstein Marc Stadler Ludwig Wilkens Jun Li Markus Kalesse Przemyslaw Bozko Ruben R. Plentz Haprolid Inhibits Tumor Growth of Hepatocellular Carcinoma through Rb/E2F and Akt/mTOR Inhibition Cancers hcc haprolid rb/e2f akt/mtor emt cell cycle apoptosis |
| title | Haprolid Inhibits Tumor Growth of Hepatocellular Carcinoma through Rb/E2F and Akt/mTOR Inhibition |
| title_full | Haprolid Inhibits Tumor Growth of Hepatocellular Carcinoma through Rb/E2F and Akt/mTOR Inhibition |
| title_fullStr | Haprolid Inhibits Tumor Growth of Hepatocellular Carcinoma through Rb/E2F and Akt/mTOR Inhibition |
| title_full_unstemmed | Haprolid Inhibits Tumor Growth of Hepatocellular Carcinoma through Rb/E2F and Akt/mTOR Inhibition |
| title_short | Haprolid Inhibits Tumor Growth of Hepatocellular Carcinoma through Rb/E2F and Akt/mTOR Inhibition |
| title_sort | haprolid inhibits tumor growth of hepatocellular carcinoma through rb e2f and akt mtor inhibition |
| topic | hcc haprolid rb/e2f akt/mtor emt cell cycle apoptosis |
| url | https://www.mdpi.com/2072-6694/12/3/615 |
| work_keys_str_mv | AT junxing haprolidinhibitstumorgrowthofhepatocellularcarcinomathroughrbe2fandaktmtorinhibition AT vikasbhuria haprolidinhibitstumorgrowthofhepatocellularcarcinomathroughrbe2fandaktmtorinhibition AT khaccuongbui haprolidinhibitstumorgrowthofhepatocellularcarcinomathroughrbe2fandaktmtorinhibition AT mailythinguyen haprolidinhibitstumorgrowthofhepatocellularcarcinomathroughrbe2fandaktmtorinhibition AT zexihu haprolidinhibitstumorgrowthofhepatocellularcarcinomathroughrbe2fandaktmtorinhibition AT chihjenhsieh haprolidinhibitstumorgrowthofhepatocellularcarcinomathroughrbe2fandaktmtorinhibition AT kathrinwittstein haprolidinhibitstumorgrowthofhepatocellularcarcinomathroughrbe2fandaktmtorinhibition AT marcstadler haprolidinhibitstumorgrowthofhepatocellularcarcinomathroughrbe2fandaktmtorinhibition AT ludwigwilkens haprolidinhibitstumorgrowthofhepatocellularcarcinomathroughrbe2fandaktmtorinhibition AT junli haprolidinhibitstumorgrowthofhepatocellularcarcinomathroughrbe2fandaktmtorinhibition AT markuskalesse haprolidinhibitstumorgrowthofhepatocellularcarcinomathroughrbe2fandaktmtorinhibition AT przemyslawbozko haprolidinhibitstumorgrowthofhepatocellularcarcinomathroughrbe2fandaktmtorinhibition AT rubenrplentz haprolidinhibitstumorgrowthofhepatocellularcarcinomathroughrbe2fandaktmtorinhibition |