Haprolid inhibits tumor growth of hepatocellular carcinoma through Rb/E2F and Akt/mTOR inhibition

Publikation: Beitrag in FachzeitschriftArtikelForschungPeer-Review

Autoren

  • 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

Externe Organisationen

  • Eberhard Karls Universität Tübingen
  • University of Science and Technology of China
  • Helmholtz-Zentrum für Infektionsforschung GmbH (HZI)
  • Klinikum Bremen-Nord
  • Medizinische Hochschule Hannover (MHH)
Forschungs-netzwerk anzeigen

Details

OriginalspracheEnglisch
Aufsatznummer615
FachzeitschriftCancers
Jahrgang12
Ausgabenummer3
PublikationsstatusVeröffentlicht - 6 März 2020

Abstract

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.

ASJC Scopus Sachgebiete

Ziele für nachhaltige Entwicklung

Zitieren

Haprolid inhibits tumor growth of hepatocellular carcinoma through Rb/E2F and Akt/mTOR inhibition. / Xing, Jun; Bhuria, Vikas; Bui, Khac Cuong et al.
in: Cancers, Jahrgang 12, Nr. 3, 615, 06.03.2020.

Publikation: Beitrag in FachzeitschriftArtikelForschungPeer-Review

Xing, J, Bhuria, V, Bui, KC, Nguyen, MLT, Hu, Z, Hsieh, CJ, Wittstein, K, Stadler, M, Wilkens, L, Li, J, Kalesse, M, Bozko, P & Plentz, RR 2020, 'Haprolid inhibits tumor growth of hepatocellular carcinoma through Rb/E2F and Akt/mTOR inhibition', Cancers, Jg. 12, Nr. 3, 615. https://doi.org/10.3390/cancers12030615
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. (2020). Haprolid inhibits tumor growth of hepatocellular carcinoma through Rb/E2F and Akt/mTOR inhibition. Cancers, 12(3), Artikel 615. https://doi.org/10.3390/cancers12030615
Xing J, Bhuria V, Bui KC, Nguyen MLT, Hu Z, Hsieh CJ et al. Haprolid inhibits tumor growth of hepatocellular carcinoma through Rb/E2F and Akt/mTOR inhibition. Cancers. 2020 Mär 6;12(3):615. doi: 10.3390/cancers12030615
Xing, Jun ; Bhuria, Vikas ; Bui, Khac Cuong et al. / Haprolid inhibits tumor growth of hepatocellular carcinoma through Rb/E2F and Akt/mTOR inhibition. in: Cancers. 2020 ; Jahrgang 12, Nr. 3.
Download
@article{4705249a1dff41c49c4b1b084741670d,
title = "Haprolid inhibits tumor growth of hepatocellular carcinoma through Rb/E2F and Akt/mTOR inhibition",
abstract = "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.",
keywords = "Akt/mTOR, Apoptosis, Cell cycle, EMT, Haprolid, HCC, Rb/E2F",
author = "Jun Xing and Vikas Bhuria and Bui, {Khac Cuong} and Nguyen, {Mai Ly Thi} and Zexi Hu and Hsieh, {Chih Jen} and Kathrin Wittstein and Marc Stadler and Ludwig Wilkens and Jun Li and Markus Kalesse and Przemyslaw Bozko and Plentz, {Ruben R.}",
note = "Funding information: This work was supported by China Scholarship Council [grant numbers 201608080176]. We acknowledge support by Open Access Publishing Fund of University of T{\"u}bingen.",
year = "2020",
month = mar,
day = "6",
doi = "10.3390/cancers12030615",
language = "English",
volume = "12",
number = "3",

}

Download

TY - JOUR

T1 - Haprolid inhibits tumor growth of hepatocellular carcinoma through Rb/E2F and Akt/mTOR inhibition

AU - Xing, Jun

AU - Bhuria, Vikas

AU - Bui, Khac Cuong

AU - Nguyen, Mai Ly Thi

AU - Hu, Zexi

AU - Hsieh, Chih Jen

AU - Wittstein, Kathrin

AU - Stadler, Marc

AU - Wilkens, Ludwig

AU - Li, Jun

AU - Kalesse, Markus

AU - Bozko, Przemyslaw

AU - Plentz, Ruben R.

N1 - Funding information: This work was supported by China Scholarship Council [grant numbers 201608080176]. We acknowledge support by Open Access Publishing Fund of University of Tübingen.

PY - 2020/3/6

Y1 - 2020/3/6

N2 - 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.

AB - 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.

KW - Akt/mTOR

KW - Apoptosis

KW - Cell cycle

KW - EMT

KW - Haprolid

KW - HCC

KW - Rb/E2F

UR - http://www.scopus.com/inward/record.url?scp=85081238518&partnerID=8YFLogxK

U2 - 10.3390/cancers12030615

DO - 10.3390/cancers12030615

M3 - Article

AN - SCOPUS:85081238518

VL - 12

JO - Cancers

JF - Cancers

IS - 3

M1 - 615

ER -

Von denselben Autoren