Mitochondrial dysfunction-induced amphiregulin upregulation mediates chemo-resistance and cell migration in HepG2 cells

Abstract

The aim of this study was to investigate the contribution of mitochondrial dysfunction to chemoresistance and migration of hepatoma cells. We found that inhibition of mitochondrial respiration and mitochondrial DNA (mtDNA) depletion resulted in induction of amphiregulin (AR) expression in HepG2 cells. Upon oligomycin treatment of HepG2 cells, the cytosolic Ca(2+) was significantly raised after 30 min, and the intracellular level of reactive oxygen species (ROS) was elevated 2.2-fold after 4 h. Moreover, the condition medium of oligomycin-treated HepG2 cells was found to stimulate the migration of SK-Hep-1 cells. On the other hand, oligomycin-induced cisplatin-resistance and cell migration of HepG2 cells were attenuated by AR-specific RNA interference (#L-017435, Dharmacon) and a neutralizing antibody (MAB262, R&D Systems), respectively. Together, these findings suggest that mitochondrial dysfunction induced Ca(2+) mobilization, and ROS overproduction, which modulated the chemo-resistance and migration of hepatoma cells through the induction and activation of AR.

Mitochondrial Respiratory Dysfunction Induces Claudin-1 Expression via Reactive Oxygen Species-mediated Heat Shock Factor 1 Activation, Leading to Hepatoma Cell Invasiveness

“…Therefore, they are considered a metabolic hallmark of cancer. Although the contribution of mitochondrial defects to cancer development, such as tumor angiogenesis, metastasis, and chemoresistance, has often been reported (6,10,11,(37)(38)(39), it is unclear how mitochondrial impairment regulates tumor progression. One plausible explanation is that an altered mitochondrial metabolism communicates with the nucleus through "mitochondrial retrograde signaling."…”

Role of mitochondrial dysfunction in cancer progression

“…55 Mitochondrial respiration defects in cancer cells cause activation of the Akt survival pathway and contribute to drug resistance through a redox mediated mechanism. 56 We also found that chemical impairment of the mitochondrial respiratory chain enhances cisplatin-resistance in human HepG2 cells through up-regulated expression and secretion of amphiregulin 57 and in human gastric cancer cells through a ROS-mediated regulation. 58 In addition, mtDNA copy number might affect hormone dependence in prostate cancer cells 59 and breast cancer cells.…”

“…86 Moreover, mitochondrial dysfunctions caused by various respiration inhibitors have been shown to promote cell migration via ROS-enhanced b5-integrin expression in gastric cancer SC-M1 cells 58 or ROS-mediated upregulation of amphiregulin in human hepatoma HepG2 cells. 57 In addition to ROS, Ca 2þ was found to up-regulate amphiregulin and induce chemo-resistance and migration of human hepatoma HepG2 cells. 57 Moreover, elevated cytosolic Ca 2þ was found in cancer cells with mtDNA depletion by ethidium bromide 166 and was involved in the mtDNA depletion-induced expression of the invasive markers, cathepsin L and TGFb1 as well as the invasive phenotype.…”

“…62 Depletion of mtDNA in breast cancer cells by expressing mutant mitochondrial DNA polymerase g increases Matrigel invasion. 64 In addition, chemical impairment of the mitochondrial respiratory chain in HepG2 cells enhances their migratory phenotype through the overexpression and secretion of amphiregulin by an autocrine or paracrine loop, 57 and overexpression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1a) to promote mitochondrial biogenesis in HepG2 cells can markedly repress cell migration through the upregulation of E-cadherin expression. 65,66 We also found that chemical impairment of the mitochondrial respiratory chain in human gastric cancer cells enhances cell migration through ROS-induced integrin b5 expression.…”

Amphiregulin as a Novel Resistance Factor for Amrubicin in Lung Cancer Cells

“…AREG overexpression provides self-sufficient growth and survival signals in lung carcinoma cells (15). AREG up-regulation has been associated with resistance to chemotherapy, such as doxorubicin and cisplatin in liver cancer cells (16,17) and cisplatin in breast cancer cells (18). AREG inhibits EGFR tyrosine kinase inhibitor (TKI)-induced apoptosis in NSCLC cells (15).…”