TRAIL Inhibits Tumor Growth but Is Nontoxic to Human Hepatocytes in Chimeric Mice

Hao, Chunhai; Song, Jin H.; Hsi, Belinda; Lewis, Jamie; Song, Doyoun K.; Petruk, Kenneth C.; Tyrrell, D. Lorne; Kneteman, Norman M.

doi:10.1158/0008-5472.can-04-2599

Cited by 139 publications

(108 citation statements)

References 19 publications

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“…18,19 However, recent studies of TRAIL function under physiological and pathological conditions, especially inflammatory conditions, have raised concerns about the TRAIL-based therapy. Although normal hepatocytes appear to be resistant to TRAIL, 20 our previous studies revealed that HBV infection and HBx protein expression sensitized hepatocytes to TRAIL-induced apoptosis. 6 Here we showed that HBc, another viral protein encoded by HBV, played an opposite role in TRAIL-induced hepatocyte apoptosis.…”

Section: Discussionmentioning

confidence: 85%

Hepatitis B virus core protein inhibits TRAIL-induced apoptosis of hepatocytes by blocking DR5 expression

Liang

Liu

et al. 2008

Cell Death Differ

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Hepatitis B virus (HBV) causes chronic hepatitis in hundreds of millions of people worldwide, which can eventually lead to hepatocellular carcinoma (HCC). The molecular mechanisms underlying HBV persistence are not well understood. TRAIL, the TNF-related apoptosis-inducing ligand, has recently been implicated in hepatocyte death during HBV infection. We report here that the HBV core protein (HBc) is a potent inhibitor of TRAIL-induced apoptosis. Overexpressing HBc significantly decreased TRAIL-induced apoptosis of human hepatoma cells, whereas knocking-down HBc expression in hepatoma cells transfected with HBV genome enhanced it. When present in the same cell, HBc blocked the pro-apoptotic effect of the HBV X protein (HBx). The resistance of HBc-expressing cells to TRAIL-induced apoptosis was associated with a significant reduction in death receptor 5 (DR5) expression. Upon transfection, HBc significantly repressed the promoter activity of the human DR5 gene. Importantly, HBc gene transfer inhibited hepatocyte death in a mouse model of HBV-induced hepatitis; and in patients with chronic hepatitis, DR5 expression in the liver was significantly reduced. These results indicate that HBc may prevent hepatocytes from TRAIL-induced apoptosis by blocking DR5 expression, which in turn contributes to the development of chronic hepatitis and HCC. They also call into question the potential side effects of HBc-based vaccines. Hepatitis B virus (HBV) infection remains to be a major health problem worldwide despite the availability of an effective vaccine. More than 350 million people are chronically infected with HBV who are at a high risk of developing hepatitis, cirrhosis and hepatocellular carcinoma. 1 To date, the molecular mechanisms of chronic HBV infection have not been elucidated in detail. Recent studies suggest that resistance of HBV-infected hepatocytes to apoptosis may contribute to the development of chronic hepatitis. 2 Apoptosis of hepatocytes during HBV infection is mediated by several molecular pathways, which involve at least three members of the TNF superfamily, that is, TNF, Fas ligand (FasL) and TRAIL. Unlike TNF and FasL, TRAIL preferentially induces apoptosis of tumor cells and virus-infected cells but not normal cells. [3][4][5] Blocking the TRAIL pathway using soluble death receptor 5 (DR5) significantly ameliorates liver inflammation in a mouse model of hepatitis B. 6 Interestingly, two HBV proteins, HBV X (HBx) 5 and truncated middle hepatitis B surface protein (MHBs(t)), 7 were recently found to sensitize hepatocytes to TRAIL-induced apoptosis.The TRAIL apoptotic pathway is strictly controlled at both the receptor and intracellular signaling levels. Five receptors for TRAIL have been identified, including two death receptors (DR4 and DR5, also known as TRAIL-R1 and TRAIL-R2, respectively) and two decoy receptors (decoy receptor 1(DcR1, TRAIL-R3, and TRID) and decoy receptor 2 (DcR2, TRAIL-R4, and TRUNDD)). 4,8,9 In mice, only one membrane TRAIL receptor has been identified, which shares 79% sequenc...

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Section: Discussionmentioning

confidence: 85%

Hepatitis B virus core protein inhibits TRAIL-induced apoptosis of hepatocytes by blocking DR5 expression

Liang

Liu

et al. 2008

Cell Death Differ

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“…45 Nevertheless, later studies showed that the potential of TRAIL to induce apoptosis in human hepatocytes in vitro is dependent on the recombinant form of TRAIL used 46 and that human hepatocytes transferred to SCID/Alb-uPA mice were insensitive to TRAIL in vivo. 47 In conclusion, many types of tumor cells develop resistance to TGF-␤-induced growth inhibition and concomitantly acquire the ability to release TGF-␤. 48 TRAIL resistance as well as TGF-␤ resistance may be acquired after long-term exposure or selective outgrowth of cells with such a resistance, providing a growth advantage in the course of tumor growth and dedifferentiation.…”

Section: Discussionmentioning

confidence: 96%

Transforming growth factor β can mediate apoptosis via the expression of TRAIL in human hepatoma cells

et al. 2005

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Transforming growth factor ␤ (TGF-␤) has been shown to induce apoptotic cell death in normal and transformed hepatocytes. However, the exact mechanism through which TGF-␤ induces cell death is still unknown. We examined a potential role of various death receptor/ ligand systems in TGF-␤-induced apoptosis and identified the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as a mediator of TGF-␤-induced apoptosis in hepatoma cells. TGF-␤-induced apoptosis is significantly impaired upon blockage of TRAIL. We show that TRAIL is upregulated in hepatoma cells upon treatment with TGF-␤, whereas TRAIL receptor levels remain unchanged. In conclusion, our results provide evidence that the TRAIL system is critically involved in TGF-␤-induced cell death in liver pathology. (HEPATOLOGY 2005;42:183-192.)

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“…TRAIL has been shown to induce apoptosis in TRAIL-sensitive NSCLC cell lines and inhibit the growth of the xenografts generated from the cell lines (2,6,30). However, it is reported that the majority of the NSCLC cell lines were either partially or completely resistant to TRAIL treatment (27).…”

Section: Sensitivity To Trail Of Two Nsclc Cell Lines In Vitromentioning

confidence: 99%

“…Targeted molecular therapy applied to lung cancer has rapidly developed in recent years. Due to its preferential inducibility of apoptosis in cancer cells over normal cells (1,2), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising targeted therapy drug (3)(4)(5). It is reported that TRAIL can induce apoptosis in NSCLC cell lines (6) and inhibit the growth of NSCLC xenografts (2).…”

Section: Introductionmentioning

confidence: 99%

Redistribution of DR4 and DR5 in lipid rafts accounts for the sensitivity to TRAIL in NSCLC cells

Ouyang

Yang²,

Liu³

et al. 2011

Int J Oncol

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Abstract. The selective toxicity of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) against tumor cells makes it a potential targeted drug for treating non-small cell lung carcinomas (NSCLC). However, the majority of established human NSCLC cell lines are either partially or completely resistant to TRAIL, resulting in the limitation for clinical use of rhTRAIL and its agonistic antibodies. In this study, compared to TRAIL-sensitive H460 cell line, TRAIL-resistant A549 cell line showed a similar expression level of DR5 and a higer expression level of DR4. It indicates that there is no positive correlation between the expression levels of death receptors and sensitivity to TRAIL. However, tests on A549 cells with DR4 siRNA transfection revealed that DR4-competitive binding to TRAIL could not affect the capacity of TRAIL in inducing apoptosis. Instead, further studies found that the aggregation of DR4 and DR5 in lipid rafts only occured in H460 cells with TRAIL pretreatment. It suggested that the TRAIL-induced redistribution of DR4 and DR5 in lipid rafts contributed to the sensitivity to TRAIL in TRAIL-sensitive NSCLC H460 cell line, which was also confirmed by intervention tests of the cholesterol-sequestering agent nystatin. IntroductionLung cancer is the leading cause of cancer death for both men and women over the world, and non-small cell lung carcinomas (NSCLC) constitute 75% of lung cancer. Although recent advances in the chemotherapeutic management of NSCLC have improved its prognosis, no curative therapy currently exists for advanced lung cancer patients. Accordingly, new therapeutic methods need to be developed. Targeted molecular therapy applied to lung cancer has rapidly developed in recent years. Due to its preferential inducibility of apoptosis in cancer cells over normal cells (1,2), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising targeted therapy drug (3-5). It is reported that TRAIL can induce apoptosis in NSCLC cell lines (6) and inhibit the growth of NSCLC xenografts (2). However, the majority of human NSCLC cells are resistant to TRAIL. Instead of benefiting from TRAIL treatments, patients with TRAIL-resistant tumor may probably suffer from the potential side-effects. Consequently, resistance of NSCLC cells to TRAIL-induced apoptosis is a limitation for the clinical use of both rhTRAIL and its agonistic antibodies, so it is very important to investigate the molecular mechanisms of TRAIL-resistance in NSCLC cells and to find the therapeutic agents that could switch TRAIL signals from cell survival to cell death.TRAIL is a member of the tumor necrosis factor (TNF) family (7,8) and plays a role in tumor immunosurveillance (9). It induces apoptosis in a variety of cancer cells (7,10) by interacting with its death receptors DR4 (TRAIL-R1) (11) and DR5 (TRAIL-R2) (12) on target cell surface. DR4 and DR5 contains a cytoplasmic region designated as the death domain, which is responsible for transducing the death signal. On ligand binding, DR4 or DR5 initiat...

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TRAIL Inhibits Tumor Growth but Is Nontoxic to Human Hepatocytes in Chimeric Mice

Cited by 139 publications

References 19 publications

Hepatitis B virus core protein inhibits TRAIL-induced apoptosis of hepatocytes by blocking DR5 expression

Hepatitis B virus core protein inhibits TRAIL-induced apoptosis of hepatocytes by blocking DR5 expression

Transforming growth factor β can mediate apoptosis via the expression of TRAIL in human hepatoma cells

Redistribution of DR4 and DR5 in lipid rafts accounts for the sensitivity to TRAIL in NSCLC cells

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