Survival and apoptosis: a dysregulated balance in liver cancer

Fabregat, Isabel; Roncero, César; Fernández, Margarita

doi:10.1111/j.1478-3231.2006.01409.x

Cited by 205 publications

(154 citation statements)

References 55 publications

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“…Most currently available cytotoxic drugs induce tumor death by triggering apoptosis, but many tumors have defects in the regulation of genes that control this process, thus rendering them resistant to chemotherapeutic agents. The serine/threonine kinases MAPKs (mitogen-activated protein kinases) and Akt/PKB (protein kinase B) are well-recognized mediators of cell survival in response to a number of stimuli (Nicholson and Anderson, 2002;Vivanco and Sawyers, 2002; Sebolt-Leopold and , 2004), and have been implicated to play a pivotal role in cytotoxic drugs-mediated apoptosis in HCC (Fabregat et al, 2007). Specifically, the Akt/PKB pathway and members of the Bcl-2 survival family have been studied extensively and shown to play an important anti-apoptotic role in many cancers (Nicholson and Anderson, 2002;Sebolt-Leopold and Herrera, 2004).…”

Section: Resultsmentioning

confidence: 99%

CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway

et al. 2007

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The recent discovery of cancer stem cells (CSCs) has played a pivotal role in changing our view of carcinogenesis and chemotherapy. Based on this concept, CSCs are responsible for the formation and growth of neoplastic tissue and are naturally resistant to chemotherapy, explaining why traditional chemotherapies can initially shrink a tumor but fails to eradicate it in full, allowing eventual recurrence. Recently, we identified a CSC population in hepatocellular carcinoma (HCC) characterized by their CD133 phenotype. However, the molecular mechanism by which it escapes conventional therapies remains unknown. Here, we examined the sensitivity of these cells to chemotherapeutic agents (doxorubicin and fluorouracil) and the possible mechanistic pathway by which resistance may be regulated. Purified CD133 þ HCC cells isolated from human HCC cell line and xenograft mouse models survived chemotherapy in increased proportions relative to most tumor cells which lack the CD133 phenotype; the underlying mechanism of which required the preferential expression of survival proteins involved in the Akt/PKB and Bcl-2 pathway. Treatment of CD133 þ HCC cells with an AKT1 inhibitor, specific to the Akt/PKB pathway, significantly reduced the expression of the survival proteins that was normally expressed endogenously. In addition, treatment of unsorted HCC cells with both anticancer drugs in vitro significantly enriched the CD133 þ subpopulation.In conclusion, our results show that CD133 þ HCC cells contribute to chemoresistance through preferential activation of Akt/PKB and Bcl-2 cell survival response. Targeting of this specific survival signaling pathway in CD133 þ HCC CSCs may provide a novel therapeutic model for the disease.

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Section: Resultsmentioning

confidence: 99%

CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway

et al. 2007

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“…35,36 Proteasome inhibitors, such as BZB, have been recently shown to sensitize tumor cells, including HCC cells, toward TRAIL-induced apoptosis. 23,24 These agents might be superior to other TRAIL-synergizing drugs, because inhibition of the proteasome as the central regulator of protein turnover affects multiple pathways and thus increases the likelihood that various TRAILresistance mechanisms can be bypassed.…”

Section: Discussionmentioning

confidence: 99%

Increased apoptosis induction in hepatocellular carcinoma by a novel tumor-targeted TRAIL fusion protein combined with bortezomib

et al. 2013

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As the result of an increasing incidence and a prevalent therapy resistance of hepatocellular carcinoma (HCC), there is a strong need for novel strategies to enhance treatment responses in HCC. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been proposed as a promising anticancer drug because it can selectively induce apoptosis in cancer cells, but not in healthy cells. Nevertheless, most tumor cells show TRAIL resistance, emphasizing the requirement for apoptosis-sensitizing agents and TRAIL molecules with improved tumor specificity. In this study, we employed a recombinant TRAIL molecule, in which three TRAIL protomers were expressed as a single polypeptide chain (scTRAIL), and a novel TRAIL variant, in which scTRAIL was additionally fused to an antibody fragment recognizing epidermal growth factor receptor (EGFR) to improve its HCC-targeting properties. We analyzed the proapoptotic effects of both TRAIL versions in combination with the proteasome inhibitor bortezomib (BZB) in hepatoma cells and primary human hepatocytes as well as in intact explants from HCC and healthy liver tissue. We demonstrate that EGFR-targeted TRAIL in combination with BZB induced significantly higher caspase activation and cell death in hepatoma cells, but not in primary hepatocytes. Importantly, when incubated with fresh liver explants, the combination of EGFR-targeted TRAIL and BZB displayed selective cytotoxicity for HCC, but not for tumor-free liver tissue, which could even be verified in liver explants from the same individuals. Unlike nontargeted TRAIL, EGFR-targeted TRAIL combined with BZB exerted no toxicity in liver tissues from nonalcoholic fatty liver disease patients. Conclusion: EGFRtargeted TRAIL reveals increased antitumor activity toward HCC without inducing toxicity to tumor-free liver tissue and might therefore represent a promising novel strategy for HCC treatment. (HEPATOLOGY 2013;57:625-636) H epatocellular carcinoma (HCC) is a global health problem with increasing incidence. 1 In western countries, less than 50% of patients are eligible for potential curative treatment, including resection, transplantation, or local ablation. The limited therapeutic options and its resistance to systemic chemotherapy have triggered the search for moleculartargeted therapies for liver cancer. There is evidence of aberrant activation of several signaling cascades, such as the epidermal growth factor receptor (EGFR)/

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“…The in vitro anticancer activity is due to the combined induction of the apoptotic program, G 1 arrest, and reduced DNA synthesis. The apoptotic response has been observed in response to various anticancer stimuli, including natural products (38); however, failure in HCC cure results from the development of drug resistance, the rates of HCC incidence and mortality being similar (16).…”

Section: Discussionmentioning

confidence: 99%

Autophagy inhibition enhances anthocyanin-induced apoptosis in hepatocellular carcinoma

Longo

Platini

Scardino

et al. 2008

Molecular Cancer Therapeutics

113

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Anthocyanins extracted from the berries of Phillyrea latifolia L., Pistacia lentiscus L., and Rubia peregrina L., three evergreen shrubs widely distributed in the Mediterranean area, were examined for their antioxidant and anticancer activity. The P. lentiscus anthocyanins showed the highest H 2 O 2 and 1,1-diphenyl-2-picrylhydrazil radical scavenging effects, indicating that these compounds can be considered as an alternative source of natural antioxidants for food and pharmaceutical products. Here, we also report a novel function of anthocyanins: the induction of autophagy, a process of subcellular turnover involved in carcinogenesis. Autophagy was characterized by the up-regulation of eIF2A, an autophagy inducer, and down-regulation of mTOR and Bcl-2, two autophagy inhibitors. This led to the enhanced expression of LC3-II, an autophagosome marker in mammals, and monodansylcadaverine incorporation into autolysosomes. Anthocyanin-induced autophagy switched to apoptosis, as shown by the activation of Bax, cytochrome c and caspase 3, terminal deoxynucleotide transferase -mediated dUTP nick-end labeling -positive fragmented nuclei, and cells with sub-G 1 DNA content, which were prevented by z-VAD. Inhibition of autophagy by either 3-methyladenine or Atg5 small interfering RNA enhanced anthocyanintriggered apoptosis. This provided evidence that autophagy functions as a survival mechanism in liver cancer cells against anthocyanin-induced apoptosis and a rationale for the use of autophagy inhibitors in combination with dietary chemopreventive agents. [Mol Cancer Ther 2008;7(8):2476 -85]

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Survival and apoptosis: a dysregulated balance in liver cancer

Cited by 205 publications

References 55 publications

CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway

CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway

Increased apoptosis induction in hepatocellular carcinoma by a novel tumor-targeted TRAIL fusion protein combined with bortezomib

Autophagy inhibition enhances anthocyanin-induced apoptosis in hepatocellular carcinoma

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