Mechanisms of doxorubicin resistance in hepatocellular carcinoma

Cox, Josiah; Weinman, Steven A.

doi:10.2217/hep.15.41

Cited by 124 publications

(91 citation statements)

References 147 publications

(129 reference statements)

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“…As with many chemotherapeutic agents, acquisition of resistance is a major problem. Doxorubicin resistance in human cells is due, in some cases, to upregulation of ABC transporters (multidrug resistance pumps) MRP1 (76) and MDR1/P-glycoprotein (77), but other proteins also have been implicated (78, 79). A prior study with S.…”

Section: Discussionmentioning

confidence: 99%

TOR Complex 2-Regulated Protein Kinase Fpk1 Stimulates Endocytosis via Inhibition of Ark1/Prk1-Related Protein Kinase Akl1 in Saccharomyces cerevisiae

Roelants

Leskoske

Pedersen

et al. 2017

Molecular and Cellular Biology

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Depending on the stress, plasma membrane alterations activate or inhibit yeast target of rapamycin (TOR) complex 2, which, in turn, upregulates or downregulates the activity of its essential downstream effector, protein kinase Ypk1. Through phosphorylation of multiple substrates, Ypk1 controls many processes that restore homeostasis. One such substrate is protein kinase Fpk1, which is negatively regulated by Ypk1. Fpk1 phosphorylates and stimulates flippases that translocate aminoglycerophospholipids from the outer to the inner leaflet of the plasma membrane. Fpk1 has additional roles, but other substrates were uncharacterized. We show that Fpk1 phosphorylates and inhibits protein kinase Akl1, related to protein kinases Ark1 and Prk1, which modulate the dynamics of actin patch-mediated endocytosis. Akl1 has two Fpk1 phosphorylation sites (Ark1 and Prk1 have none) and is hypophosphorylated when Fpk1 is absent. Conversely, under conditions that inactivate TORC2-Ypk1 signaling, which alleviates Fpk1 inhibition, Akl1 is hyperphosphorylated. Monitoring phosphorylation of known Akl1 substrates (Sla1 and Ent2) confirmed that Akl1 is hyperactive when not phosphorylated by Fpk1. Fpk1-mediated negative regulation of Akl1 enhances endocytosis, because an Akl1 mutant immune to Fpk1 phosphorylation causes faster dissociation of Sla1 from actin patches, confers elevated resistance to doxorubicin (a toxic compound whose entry requires endocytosis), and impedes Lucifer yellow uptake (a marker of fluid phase endocytosis). Thus, TORC2-Ypk1, by regulating Fpk1-mediated phosphorylation of Akl1, adjusts the rate of endocytosis.

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Section: Discussionmentioning

confidence: 99%

TOR Complex 2-Regulated Protein Kinase Fpk1 Stimulates Endocytosis via Inhibition of Ark1/Prk1-Related Protein Kinase Akl1 in Saccharomyces cerevisiae

Roelants

Leskoske

Pedersen

et al. 2017

Molecular and Cellular Biology

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“…One of the major reasons for the low efficacy of clinical HCC chemotherapy is the resistance to anticancer agents, such as doxorubicin [28]. In addition to its function in controlling HCC growth and apoptosis, modulation of HANR expression also significantly influenced the sensitivity of both hepatoma cells and in vivo tumors to doxorubicin.…”

Section: Discussionmentioning

confidence: 99%

“…Chemoresistance is a very thorny problem in tumor treatment, doxorubicin is one of major agents for anti-HCC [28], we investigated the role of HANR in 1μg/ml doxorubicin treated 24h to induced cell growth retardation. As expected, doxorubicin incubation significantly reduced viable cell number and the proliferative rate of both Hep3B and Huh-7 cells, which were assessed by MTT, immunoblotting and the doubling times observe assay.…”

Section: Overexpression Of Hanr Can Promotes Hcc Chemoresistance In Vmentioning

confidence: 99%

LncRNA HANR Promotes Tumorigenesis and Increase of Chemoresistance in Hepatocellular Carcinoma

Xiao

Jin

et al. 2017

Cell Physiol Biochem

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Background/Aims: Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third leading cause of cancer-related death. Critical roles for long non-coding RNAs (lncRNAs) have recently been demonstrated for a variety of cancers, including hepatocellular carcinoma. However, the effect and mechanism of lncRNAs in HCC tumorigenesis and chemoresistance have not been extensively characterized. Methods: In the current study, we have identified a HCC-expressed lncRNA termed as HANR (HCC associated long non-coding RNA). We identified HANR by microarray analysis and validated its up-regulated expression by quantitative PCR. RNA pull-down and pathway analyses were conducted to evaluate physical and functional interactions with HANR. In vivo experiments were performed to assess tumorigenesis and increase of chemoresistance. In addition, the HANR expression in HCC specimens was detected by FISH. Xenograft and orthotopic mice model was constructed to observe the effect of HANR on tumorigenesis and chemoresistance in vivo. Results: HANR was demonstrated to be up-regulated in HCC patients and HCC cell lines. Increased HANR expression in HCC predicted short survival of patients. Knock-down of HANR markedly retarded cell proliferation, suppressed HCC xenograft/orthotopic tumor growth, induced apoptosis and enhanced chemosensitivity to doxorubicin, while overexpression of HANR showed the opposite effects. It was found that HANR bind to GSKIP for regulating the phosphorylation of GSK3β in HCC. Conclusion: Our results demonstrate that HANR contributes to the development of HCC and is a promising therapeutic target for chemosensitization of HCC cells to doxorubicin, which may represent a promising therapeutic target in the future.

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“…A recent study by M Chartrain et al (2012) showed that melanoma cells enriched after temozolomide treatment showed high expression of ABCB5 channels, which increased their anticytotoxic properties and stem-like characteristics 32 . According to a study of Cox et al (2012) on the mechanism of doxorubicin resistance in liver carcinoma cells, it has been shown that in cancer cell populations, there are cells capable of pumping drugs out via the ABC transporter family 33 . These channels need ATP to pump drugs out, protecting cells from toxins.…”

Section: Discussionmentioning

confidence: 99%

Isolation of cancer stem-like cells from hepatocellular carcinoma cell line HepG2 by methods of magnetic-activated cell sorting, spheroid culture, and anti-tumor drug-resistant selection: A primary evaluation

Nguyen

et al. 2020

Prog. Stem Cell

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Introduction:Recently reported data have suggested that only a small subset of cancer cells possess the capability to initiate malignancies. These observations were based on investigation of cells within the primary tumors displaying a distinct surface marker pattern. CD133 marker is a putative hematopoietic and neuronal stem cell marker, which is also considered to be a tumorigenic marker in brain, prostate and liver. Recent studies have shown that a small population of CD133-positive cells, indeed, exists in human hepatocellular carcinoma (HCC) cell lines and primary HCC tissues. This study was aimed at isolating the cancer stem-like cells from hepatocellular carcinoma cell line HepG2 using three different methods: magnetic-activated cell sorting (MACS), spheroid culture (SC), and anti-tumor drug (ATD) resistant selection. Methods: HepG2 hepatocellular carcinoma cells were expanded to yield enough cells that could be used to isolate cancer stem-like cells by these three methods. For MACS, cancer stem-like cells were sorted using anti-CD133 monoclonal antibody. For the second method, cancer stem-like cells were enriched by selection of anti-tumor drug resistance property. Lastly, for the third method, three-dimensional (3D) culture was used to enrich for the cancer stem-like cells. The cells obtained by the three methods were expanded to obtain an adequate number of cells for confirmation of CD133 expression. Results: The expression of CD133 + cells in the three methods was found to be different. In the MACS method, the expanded CD133 + sorted cells cultured through 2 passages only contained 0.40 % CD133 + cells. In the 3D spheroid cell culture, of the population of cells there were 38.39 % that were CD133 + cells. Lastly, in the anti-tumor drug (doxorubicin at 150 nM) resistant selection, 66.22 % were CD133 + cells. Conclusion: This study shows that isolation of HepG2 derived CD133 + population by culture with doxorubicin (150 nM) yields the highest efficiency and purity of the 3 methods studied. P. Isolation of cancer stem-like cells from hepatocellular carcinoma cell lineHepG2 by methods of magneticactivated cell sorting, spheroid culture, and anti-tumor drug-resistant selection: A primary evaluation. Progress. Stem. Cell.; 7(1):279-289. 279 History •

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Mechanisms of doxorubicin resistance in hepatocellular carcinoma

Cited by 124 publications

References 147 publications

TOR Complex 2-Regulated Protein Kinase Fpk1 Stimulates Endocytosis via Inhibition of Ark1/Prk1-Related Protein Kinase Akl1 in Saccharomyces cerevisiae

TOR Complex 2-Regulated Protein Kinase Fpk1 Stimulates Endocytosis via Inhibition of Ark1/Prk1-Related Protein Kinase Akl1 in Saccharomyces cerevisiae

LncRNA HANR Promotes Tumorigenesis and Increase of Chemoresistance in Hepatocellular Carcinoma

Isolation of cancer stem-like cells from hepatocellular carcinoma cell line HepG2 by methods of magnetic-activated cell sorting, spheroid culture, and anti-tumor drug-resistant selection: A primary evaluation

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