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Modulation of the unfolded protein response impedes tumor cell adaptation to proteotoxic stress: a PERK for hepatocellular carcinoma therapy.

Vandewynckel YP, Laukens D, Bogaerts E, Paridaens A, Van den Bussche A, Verhelst X, Van Steenkiste C, Descamps B, Vanhove C, Libbrecht L, De Rycke R, Lambrecht BN, Geerts A, Janssens S, Van Vlierberghe H - Hepatol Int (2014)

Bottom Line: Consistent with the UPR activation, electron microscopy demonstrated ER expansion and reorganization in HCC cells in vivo.Strikingly, under ER stress or hypoxia, the Perk inhibitor and not the Ire1 inhibitor reduced cell viability and proliferation via escalating proteotoxic stress in vitro.We provide the first evaluation of the UPR dynamics in a long-term cancer model and identified a small molecule inhibitor of Perk as a promising strategy for HCC therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatology and Gastroenterology, Ghent University, De Pintelaan 185, 1K12 IE, 9000 Ghent, Belgium.

ABSTRACT

Background: Functional disturbances of the endoplasmic reticulum (ER) lead to activation of the unfolded protein response (UPR), which is involved in the consecutive steps of carcinogenesis. In human hepatocellular carcinoma (HCC), the UPR is shown to be activated; however, little is known about the UPR kinetics and effects of UPR modulation in HCC.

Methods: We sequentially monitored the UPR over time in an orthotopic mouse model for HCC and explored the effects of UPR modulation on cell viability and proliferation in vitro and in the mouse model.

Results: The expression of ER-resident chaperones peaked during tumor initiation and increased further during tumor progression, predominantly within the nodules. A peak in Ire1 signaling was observed during tumor initiation. The Perk pathway was activated during tumor progression, and the proapoptotic target Chop was upregulated from week 5 and continued to rise, especially in the tumors. The Atf6 pathway was modestly activated only after tumor initiation. Consistent with the UPR activation, electron microscopy demonstrated ER expansion and reorganization in HCC cells in vivo. Strikingly, under ER stress or hypoxia, the Perk inhibitor and not the Ire1 inhibitor reduced cell viability and proliferation via escalating proteotoxic stress in vitro. Notably, the Perk inhibitor significantly decreased tumor burden in the mouse model.

Conclusion: We provide the first evaluation of the UPR dynamics in a long-term cancer model and identified a small molecule inhibitor of Perk as a promising strategy for HCC therapy.

No MeSH data available.


Related in: MedlinePlus

Transmission electron microscopy of saline- and tunicamycin-treated livers and DEN-induced tumors of the mouse model. a Expansion of the endoplasmic reticulum (ER; arrows) in HCC cells (middle panel) compared with saline-treated livers (left panel). Dilated ER in the liver of mice that received tunicamycin for 72 h (right panel). CF, collagen fibers. Tunicamycin-induced lipid droplets are indicated by arrowheads. b Reorganization of the endoplasmic reticulum after 30 weeks of DEN administration. DEN-induced HCC: hepatocellular carcinoma nodules isolated from the diethylnitrosamine-treated mouse liver
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Fig3: Transmission electron microscopy of saline- and tunicamycin-treated livers and DEN-induced tumors of the mouse model. a Expansion of the endoplasmic reticulum (ER; arrows) in HCC cells (middle panel) compared with saline-treated livers (left panel). Dilated ER in the liver of mice that received tunicamycin for 72 h (right panel). CF, collagen fibers. Tunicamycin-induced lipid droplets are indicated by arrowheads. b Reorganization of the endoplasmic reticulum after 30 weeks of DEN administration. DEN-induced HCC: hepatocellular carcinoma nodules isolated from the diethylnitrosamine-treated mouse liver

Mentions: Electron microscopy of the tumors in the mouse model at W30 revealed an extensive expanded ribosome-bound ER in a lamellar pattern (Fig. 3a, middle panel) in the HCC cells compared with the ER in the hepatocytes of saline-treated mice (Fig. 3a, left panel). The liver of mice treated with the ER stress inducer tunicamycin showed extremely dilated ER in the hepatocytes (Fig. 3a, right panel). Interestingly, some HCC cells demonstrated a remarkable ER reorganization with disruption of ribosome-bound ER and extension of smooth ER (Fig. 3b). These observations provide structural evidence for the hypothesis that DEN-induced hepatocarcinogenesis leads to ER stress.Fig. 3


Modulation of the unfolded protein response impedes tumor cell adaptation to proteotoxic stress: a PERK for hepatocellular carcinoma therapy.

Vandewynckel YP, Laukens D, Bogaerts E, Paridaens A, Van den Bussche A, Verhelst X, Van Steenkiste C, Descamps B, Vanhove C, Libbrecht L, De Rycke R, Lambrecht BN, Geerts A, Janssens S, Van Vlierberghe H - Hepatol Int (2014)

Transmission electron microscopy of saline- and tunicamycin-treated livers and DEN-induced tumors of the mouse model. a Expansion of the endoplasmic reticulum (ER; arrows) in HCC cells (middle panel) compared with saline-treated livers (left panel). Dilated ER in the liver of mice that received tunicamycin for 72 h (right panel). CF, collagen fibers. Tunicamycin-induced lipid droplets are indicated by arrowheads. b Reorganization of the endoplasmic reticulum after 30 weeks of DEN administration. DEN-induced HCC: hepatocellular carcinoma nodules isolated from the diethylnitrosamine-treated mouse liver
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4289530&req=5

Fig3: Transmission electron microscopy of saline- and tunicamycin-treated livers and DEN-induced tumors of the mouse model. a Expansion of the endoplasmic reticulum (ER; arrows) in HCC cells (middle panel) compared with saline-treated livers (left panel). Dilated ER in the liver of mice that received tunicamycin for 72 h (right panel). CF, collagen fibers. Tunicamycin-induced lipid droplets are indicated by arrowheads. b Reorganization of the endoplasmic reticulum after 30 weeks of DEN administration. DEN-induced HCC: hepatocellular carcinoma nodules isolated from the diethylnitrosamine-treated mouse liver
Mentions: Electron microscopy of the tumors in the mouse model at W30 revealed an extensive expanded ribosome-bound ER in a lamellar pattern (Fig. 3a, middle panel) in the HCC cells compared with the ER in the hepatocytes of saline-treated mice (Fig. 3a, left panel). The liver of mice treated with the ER stress inducer tunicamycin showed extremely dilated ER in the hepatocytes (Fig. 3a, right panel). Interestingly, some HCC cells demonstrated a remarkable ER reorganization with disruption of ribosome-bound ER and extension of smooth ER (Fig. 3b). These observations provide structural evidence for the hypothesis that DEN-induced hepatocarcinogenesis leads to ER stress.Fig. 3

Bottom Line: Consistent with the UPR activation, electron microscopy demonstrated ER expansion and reorganization in HCC cells in vivo.Strikingly, under ER stress or hypoxia, the Perk inhibitor and not the Ire1 inhibitor reduced cell viability and proliferation via escalating proteotoxic stress in vitro.We provide the first evaluation of the UPR dynamics in a long-term cancer model and identified a small molecule inhibitor of Perk as a promising strategy for HCC therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatology and Gastroenterology, Ghent University, De Pintelaan 185, 1K12 IE, 9000 Ghent, Belgium.

ABSTRACT

Background: Functional disturbances of the endoplasmic reticulum (ER) lead to activation of the unfolded protein response (UPR), which is involved in the consecutive steps of carcinogenesis. In human hepatocellular carcinoma (HCC), the UPR is shown to be activated; however, little is known about the UPR kinetics and effects of UPR modulation in HCC.

Methods: We sequentially monitored the UPR over time in an orthotopic mouse model for HCC and explored the effects of UPR modulation on cell viability and proliferation in vitro and in the mouse model.

Results: The expression of ER-resident chaperones peaked during tumor initiation and increased further during tumor progression, predominantly within the nodules. A peak in Ire1 signaling was observed during tumor initiation. The Perk pathway was activated during tumor progression, and the proapoptotic target Chop was upregulated from week 5 and continued to rise, especially in the tumors. The Atf6 pathway was modestly activated only after tumor initiation. Consistent with the UPR activation, electron microscopy demonstrated ER expansion and reorganization in HCC cells in vivo. Strikingly, under ER stress or hypoxia, the Perk inhibitor and not the Ire1 inhibitor reduced cell viability and proliferation via escalating proteotoxic stress in vitro. Notably, the Perk inhibitor significantly decreased tumor burden in the mouse model.

Conclusion: We provide the first evaluation of the UPR dynamics in a long-term cancer model and identified a small molecule inhibitor of Perk as a promising strategy for HCC therapy.

No MeSH data available.


Related in: MedlinePlus