Abstract
The goals of the present study were to investigate the mechanism of hypoxia-mediated chemoresistance in liver cancer cells and tumorigenic hepatic progenitor (oval) cells and to determine whether disrupting an Akt/hypoxia-inducible factor-1alpha (HIF-1alpha)/platelet-derived growth factor (PDGF)-BB autocrine loop can enhance chemotherapeutic efficacy in hypoxia. Five hepatocellular carcinoma (HCC) cell lines and two hepatic progenitor cell lines were treated in vitro with cisplatin under both normoxic and hypoxic conditions. To generate ischemic hypoxia for tumor cells in vivo, hepatic artery ligation was applied to an orthotopic HCC model. Cisplatin and YC1, which is a HIF-1alpha inhibitor, were administered by portal vein and intratumoral injections, respectively. Cell viability was higher under hypoxic than normoxic conditions. HIF-1alpha and Akt were up-regulated under hypoxic conditions, forming an autocrine signaling loop with PDGF-BB. Akt/HIF-1alpha/PDGF-BB signaling regulated Akt to confer cisplatin resistance to HCC cell lines in vitro. This autocrine signaling loop also contributed to chemoresistance in the tumorigenic hepatic progenitor cell line PIL2 under hypoxic conditions but not in the nontumorigenic cell line PIL4. In an orthotopic HCC model, combining blockade of HIF-1alpha activity with ischemic hypoxia significantly enhanced the efficacy of chemotherapy, leading to suppression of tumor growth and prolongation of animal survival. Blockade of Akt/HIF-1alpha/PDGF-BB autocrine signaling could enhance the chemosensitivity of liver cancer cells and tumorigenic hepatic progenitor cells under hypoxic conditions and thus provide an effective therapeutic strategy for HCC.
Highlights
Hepatocellular carcinoma (HCC) is one of the five most common malignancies in the world and is increasing in incidence in both Asian and western countries [1]
To determine whether the Akt/hypoxia-inducible factor-1α (HIF-1α)/platelet-derived growth factor (PDGF)-BB autocrine loop is unique to HCC cells, we evaluated its contribution to cisplatin resistance in tumorigenic (PIL2) and nontumorigenic (PIL4) hepatic progenitor cell lines
This study provides evidence that the Akt pathway is important in protecting HCC cells from the cytotoxic effects of cisplatin under hypoxic conditions and suggests that multidrug resistance (MDR) genes and the glutathione system are not involved
Summary
Hepatocellular carcinoma (HCC) is one of the five most common malignancies in the world and is increasing in incidence in both Asian and western countries [1]. Targeting signaling molecules, such as hypoxia-inducible factor-1α and plateletderived growth factor, within the loop can enhance the chemosensitivity This preclinical study by combining chemotherapy with molecular target therapy shows a promising result. Other studies have shown that the transcription factor hypoxia-inducible factor-1α (HIF1α) and its downstream gene products [e.g., MDR1 and vascular endothelial growth factor (VEGF)] were responsible for drug resistance [12, 13] and angiogenesis under hypoxic conditions [14] It is not well known whether there is any crosstalk among these proposed mechanisms for hypoxia-induced chemoresistance. The “cancer stem cells” hypothesis is rapidly gaining acceptance This hypothesis posits that cancer stem cells, which represent a reservoir of self-sustaining cells with the capacity for self-renewal and tumor propagation, arise from mutated normal stem cells or progenitor cells [15, 16]. Both tumorigenic (PIL2) and nontumorigenic (PIL4) mouse oval cell lines were established to study the role of oval cells in carcinogenesis [21]
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