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Rewiring Lipid Metabolism by Targeting PCSK9 and HMGCR to Treat Liver Cancer

Alannan, Malak, Trézéguet, Véronique, Amoêdo, Nivea Dias, Rossignol, Rodrigue, Mahfouf, Walid, Rezvani, Hamid Reza, Dittrich-Domergue, Franziska, Moreau, Patrick, Lacomme, Sabrina, Gontier, Etienne, Grosset, Christophe F., Badran, Bassam, Fayyad-Kazan, Hussein, Merched, Aksam J.·2022·Cancers
DOI 10.3390/cancers15010003PMC PMC9817797
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Abstract

Alterations in lipid handling are an important hallmark in cancer. Our aim here is to target key metabolic enzymes to reshape the oncogenic lipid metabolism triggering irreversible cell breakdown. We targeted the key metabolic player proprotein convertase subtilisin/kexin type 9 (PCSK9) using a pharmacological inhibitor (R-IMPP) alone or in combination with 3-hydroxy 3-methylglutaryl-Coenzyme A reductase (HMGCR) inhibitor, simvastatin. We assessed the effect of these treatments using 3 hepatoma cell lines, Huh6, Huh7 and HepG2 and a tumor xenograft in chicken choriorallantoic membrane (CAM) model. PCSK9 deficiency led to dose-dependent inhibition of cell proliferation in all cell lines and a decrease in cell migration. Co-treatment with simvastatin presented synergetic anti-proliferative effects. At the metabolic level, mitochondrial respiration assays as well as the assessment of glucose and glutamine consumption showed higher metabolic adaptability and surge in the absence of PCSK9. Enhanced lipid uptake and biogenesis led to excessive accumulation of intracellular lipid droplets as revealed by electron microscopy and metabolic tracing. Using xenograft experiments in CAM model, we further demonstrated the effect of anti-PCSK9 treatment in reducing tumor aggressiveness. Targeting PCSK9 alone or in combination with statins deserves to be considered as a new therapeutic option in liver cancer clinical applications.

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Figure 1 Lipid metabolic changes in liver cancer. (A) Control of the lipid metabolism by the transcription factor SREBP2. (1) SREBP2 is a transcription factor that regulates the expression of PCSK9 and HMGCR genes (2) The synthesis of PCSK9 is regulated transcriptionally by SREBP-2. Once translated, it will travel through the endoplasmic reticulum (ER) and Golgi apparatus for maturation before being secreted. (3) Lipid uptake: In response to high blood cholesterol, LDLR expressed on the cell surface will bind to LDL-cholesterol (LDL-C) and will be internalized in an autosomal recessive hypercholesterolemia (ARH)-dependent manner via clathrin-coated endosomes. Inside the endosomes, LDL-C will dissociate from the receptor and will be directed toward lysosomal degradation, whilst LDLR will be recycled back to the cell surface. (4) Cholesterol synthesis: HMGCR is the rate-limiting enzyme that catalyzes the de novo synthesis of cholesterol to increase its levels in response to a decrease in the intracellular levels of cholesterol. (5) Extracellular and (6) intracellular pathway regulation of LDLR by PCSK9: in both pathways, PCSK9 binds to the epidermal growth factor (EGF)-like domain of LDLR and targets it to lysosomal degradation instead of recycling. (B) SREBF2 gene expression upregulation in 2 transcriptomic datasets and its correlation to PCSK9 and HMGCR genes generated from R2: Genomics Analysis and Visualization Platform “http://r2.amc.nl” (accessed on 23 September 2022). Upper histogram, hepatocellular carcinoma (HCC): Wu—134—MAS 5.0—u133p2. Lower histogram, hepatoblastoma (HB): López-Terrada—55—fRMA—u133p2. Unpaired t-test, ** p < 0.01; **** p < 0.0001. Each histogram is followed by two-tailed pearson correlation which shows a positive correlation between SREBF2 and PCSK9 as well as SREBF2 and HMGCR gene expression in the same datasets. (C) Normalized gene expression of SREBF2, PCSK9 and HMGCR in three liver cancer cell lines (HepG2, Huh6 and Huh7) and one normal cell line (THLE2). (D) PCSK9 and HMGCR staining of HB tumoral (T) tissues were compared to non-tumoral (NT) tissues from the same patients. The staining in metastatic (M) tissues (diaphragm) was also checked. Samples were collected as described in materials and methods. The black bars represent 20 µm.
Figure 1 Lipid metabolic changes in liver cancer. (A) Control of the lipid metabolism by the transcription factor SREBP2. (1) SREBP2 is a transcription factor that regulates the expression of PCSK9 and HMGCR genes (2) The synthesis of PCSK9 is regulated transcriptionally by SREBP-2. Once translated, it will travel through the endoplasmic reticulum (ER) and Golgi apparatus for maturation before being secreted. (3) Lipid uptake: In response to high blood cholesterol, LDLR expressed on the cell surface will bind to LDL-cholesterol (LDL-C) and will be internalized in an autosomal recessive hypercholesterolemia (ARH)-dependent manner via clathrin-coated endosomes. Inside the endosomes, LDL-C will dissociate from the receptor and will be directed toward lysosomal degradation, whilst LDLR will be recycled back to the cell surface. (4) Cholesterol synthesis: HMGCR is the rate-limiting enzyme that catalyzes the de novo synthesis of cholesterol to increase its levels in response to a decrease in the intracellular levels of cholesterol. (5) Extracellular and (6) intracellular pathway regulation of LDLR by PCSK9: in both pathways, PCSK9 binds to the epidermal growth factor (EGF)-like domain of LDLR and targets it to lysosomal degradation instead of recycling. (B) SREBF2 gene expression upregulation in 2 transcriptomic datasets and its correlation to PCSK9 and HMGCR genes generated from R2: Genomics Analysis and Visualization Platform “http://r2.amc.nl” (accessed on 23 September 2022). Upper histogram, hepatocellular carcinoma (HCC): Wu—134—MAS 5.0—u133p2. Lower histogram, hepatoblastoma (HB): López-Terrada—55—fRMA—u133p2. Unpaired t-test, ** p < 0.01; **** p < 0.0001. Each histogram is followed by two-tailed pearson correlation which shows a positive correlation between SREBF2 and PCSK9 as well as SREBF2 and HMGCR gene expression in the same datasets. (C) Normalized gene expression of SREBF2, PCSK9 and HMGCR in three liver cancer cell lines (HepG2, Huh6 and Huh7) and one normal cell line (THLE2). (D) PCSK9 and HMGCR staining of HB tumoral (T) tissues were compared to non-tumoral (NT) tissues from the same patients. The staining in metastatic (M) tissues (diaphragm) was also checked. Samples were collected as described in materials and methods. The black bars represent 20 µm.CC BY · PubMed Central
Figure 2 Effect of pharmacological inhibition of PCSK9 and HMGCR on cellular proliferation. (A) Inhibition of PCSK9 protein level by R-IMPP. Huh7 and HepG2 cells were treated with 10 and 30 μM of R-IMPP, whilst Huh6 cells were treated with 10 μM of R-IMPP. PCSK9 protein level was evaluated by Western blot in these 2 conditions 24, 48 and 72 h after treatment. Internal GAPDH was used for protein normalization (n = 3). NT: non-treated; D: DMSO; R: R-IMPP. (B) Dose-dependent inhibition of cell growth by R-IMPP as evaluated by MTS analyses. IC50 at day 3 is given for each cell line. (C) Proliferation was evaluated up to 5 days after SV treatment except for Huh6 where the experiment was stopped at day 3 because of the extensive cell death at this time point. IC50 at day 3 is given for each cell. (D) Effect of R-IMPP treatment in combination with SV. The concentrations of SV were selected close to the IC50 data from (C) (25 μM SV for Huh7 and HepG2 and 5 μM for Huh6). * Two-way ANOVA test. * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001. Supplementary Materials: original-images of western blot figures.
Figure 2 Effect of pharmacological inhibition of PCSK9 and HMGCR on cellular proliferation. (A) Inhibition of PCSK9 protein level by R-IMPP. Huh7 and HepG2 cells were treated with 10 and 30 μM of R-IMPP, whilst Huh6 cells were treated with 10 μM of R-IMPP. PCSK9 protein level was evaluated by Western blot in these 2 conditions 24, 48 and 72 h after treatment. Internal GAPDH was used for protein normalization (n = 3). NT: non-treated; D: DMSO; R: R-IMPP. (B) Dose-dependent inhibition of cell growth by R-IMPP as evaluated by MTS analyses. IC50 at day 3 is given for each cell line. (C) Proliferation was evaluated up to 5 days after SV treatment except for Huh6 where the experiment was stopped at day 3 because of the extensive cell death at this time point. IC50 at day 3 is given for each cell. (D) Effect of R-IMPP treatment in combination with SV. The concentrations of SV were selected close to the IC50 data from (C) (25 μM SV for Huh7 and HepG2 and 5 μM for Huh6). * Two-way ANOVA test. * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001. Supplementary Materials: original-images of western blot figures.CC BY · PubMed Central
Figure 3 Effect of pharmacological inhibition of PCSK9 by R-IMPP on cellular migration. Effect of inhibition of PCSK9 by R-IMPP and/or HMGCR by SV on Huh7 cell migration in a wound healing assay using IncuCyte. Wound-healing confluence was followed for up to 24 h after treatment with 10 µM R-IMPP or 25 µM SV or a combination of both. NT refers to non-treated cells. Veh stands for R-IMPP (0.001% DMSO) and SV (0.001% ethanol) solvents. Two-way ANOVA test. ** p < 0.01; *** p < 0.001; **** p < 0.0001.
Figure 3 Effect of pharmacological inhibition of PCSK9 by R-IMPP on cellular migration. Effect of inhibition of PCSK9 by R-IMPP and/or HMGCR by SV on Huh7 cell migration in a wound healing assay using IncuCyte. Wound-healing confluence was followed for up to 24 h after treatment with 10 µM R-IMPP or 25 µM SV or a combination of both. NT refers to non-treated cells. Veh stands for R-IMPP (0.001% DMSO) and SV (0.001% ethanol) solvents. Two-way ANOVA test. ** p < 0.01; *** p < 0.001; **** p < 0.0001.CC BY · PubMed Central
Figure 4 Effect of inhibition of PCSK9 on mitochondrial respiration and metabolic pathways. (A) OCR was evaluated by the Seahorse assay in Huh7 cells, which were incubated in different media settings, as indicated. NT: non-treated. * Ordinary one-way ANOVA test. (B) Glucose and glutamine consumption as well as lactate and glutamate production by Huh7 cells treated with R-IMMP (10 μM) vs. DMSO (D10) were measured at different time intervals. * Two-way ANOVA test. * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001. (C) Viability and cytotoxicity were measured by ApotoxGlo™ Assay in Huh7 cells treated with different doses of R-IMPP for 48 h (n = 1).
Figure 4 Effect of inhibition of PCSK9 on mitochondrial respiration and metabolic pathways. (A) OCR was evaluated by the Seahorse assay in Huh7 cells, which were incubated in different media settings, as indicated. NT: non-treated. * Ordinary one-way ANOVA test. (B) Glucose and glutamine consumption as well as lactate and glutamate production by Huh7 cells treated with R-IMMP (10 μM) vs. DMSO (D10) were measured at different time intervals. * Two-way ANOVA test. * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001. (C) Viability and cytotoxicity were measured by ApotoxGlo™ Assay in Huh7 cells treated with different doses of R-IMPP for 48 h (n = 1).CC BY · PubMed Central
Figure 5 PCSK9 deficiency leads to intracellular accumulation of lipid droplets. (A) Validation of depletion of PCSK9 by shRNA silencing. Cell extracts were prepared after transduction with control shRNA (shCTR) or targeting PCSK9 (shPCSK9) of Huh6 or Huh7 or HepG2 cells. Different MOIs (multiplicity of infection) were tested: 1, 3, 5 and 10; the latter was picked for further experiments. A total of 40 µg of cell proteins was loaded per lane on an SDS-PAGE. After electrophoresis and transfer, the membrane was analyzed by Western blot using anti-PCSK9 antibodies and GAPDH antibodies for comparison of loading. The two bands observed for PCSK9 correspond to the pro-PCSK9 (74 kDa) and cleaved PCSK9 (60 kDa). (B) Confocal microscopy observation of HepG2 cells performed 48 and 72 h after transfection with PCSK9 siRNA (si1) and siCTR. Mitochondria were labeled with C/YFP using a specific lentivirus targeting system (MitoC/YFP). Phalloidin (red) and DAPI (blue) were used for microfilament and nuclear DNA staining, respectively. Arrows indicate bright mitochondria network observed more frequently when PCSK9 is silenced. (C,D) Transmission electron microscopy (TEM) photomicrographs of liver cancer cell lines transduced with specific PCSK9 shRNA (shPCSK9) or control shRNA (shCTR). Dark and dense particles seen at lower and higher magnification are lipid droplets. Stars (*) indicate PDM. Abbreviations: LD: lipid droplet; PDM: peridroplet mitochondrion. Supplementary Materials: original-images of western blot figures.
Figure 5 PCSK9 deficiency leads to intracellular accumulation of lipid droplets. (A) Validation of depletion of PCSK9 by shRNA silencing. Cell extracts were prepared after transduction with control shRNA (shCTR) or targeting PCSK9 (shPCSK9) of Huh6 or Huh7 or HepG2 cells. Different MOIs (multiplicity of infection) were tested: 1, 3, 5 and 10; the latter was picked for further experiments. A total of 40 µg of cell proteins was loaded per lane on an SDS-PAGE. After electrophoresis and transfer, the membrane was analyzed by Western blot using anti-PCSK9 antibodies and GAPDH antibodies for comparison of loading. The two bands observed for PCSK9 correspond to the pro-PCSK9 (74 kDa) and cleaved PCSK9 (60 kDa). (B) Confocal microscopy observation of HepG2 cells performed 48 and 72 h after transfection with PCSK9 siRNA (si1) and siCTR. Mitochondria were labeled with C/YFP using a specific lentivirus targeting system (MitoC/YFP). Phalloidin (red) and DAPI (blue) were used for microfilament and nuclear DNA staining, respectively. Arrows indicate bright mitochondria network observed more frequently when PCSK9 is silenced. (C,D) Transmission electron microscopy (TEM) photomicrographs of liver cancer cell lines transduced with specific PCSK9 shRNA (shPCSK9) or control shRNA (shCTR). Dark and dense particles seen at lower and higher magnification are lipid droplets. Stars (*) indicate PDM. Abbreviations: LD: lipid droplet; PDM: peridroplet mitochondrion. Supplementary Materials: original-images of western blot figures.CC BY · PubMed Central
Figure 6 14C-tracing of different neutral lipids after cell feeding with [1-14C] acetate. (A) Cells were transfected with siRNA (si1 and si2) for 72 h then fed with [1-14C] acetate. Lipid extraction was performed 1, 2 and 4 h after [1-14C] acetate feeding and radiolabeled FA, DAG and TAG amounts were measured at each time point. Average values were obtained from both PCSK9 siRNA. Assays in each cell condition were performed in triplicate. (B) Pathway of acetate and its metabolic use to buildup lipids such as FAs up to TAG and lipid droplets. Enzymes catalyzing these reactions are presented in green. Abbreviation: ACSS1/2: Acyl-CoA synthetase short chain family member 1/2; ACC: Acetyl-CoA carboxylase; ACLY: ATP citrate lyase; MCD: Malonyl-CoA decarboxylase; FASN: fatty-acid synthase; ACS: Acetyl-CoA synthetase; DGAT: diacylglycerol acyltransferase; α-KG: α-ketoglutarate.
Figure 6 14C-tracing of different neutral lipids after cell feeding with [1-14C] acetate. (A) Cells were transfected with siRNA (si1 and si2) for 72 h then fed with [1-14C] acetate. Lipid extraction was performed 1, 2 and 4 h after [1-14C] acetate feeding and radiolabeled FA, DAG and TAG amounts were measured at each time point. Average values were obtained from both PCSK9 siRNA. Assays in each cell condition were performed in triplicate. (B) Pathway of acetate and its metabolic use to buildup lipids such as FAs up to TAG and lipid droplets. Enzymes catalyzing these reactions are presented in green. Abbreviation: ACSS1/2: Acyl-CoA synthetase short chain family member 1/2; ACC: Acetyl-CoA carboxylase; ACLY: ATP citrate lyase; MCD: Malonyl-CoA decarboxylase; FASN: fatty-acid synthase; ACS: Acetyl-CoA synthetase; DGAT: diacylglycerol acyltransferase; α-KG: α-ketoglutarate.CC BY · PubMed Central
Figure 7 Depleting PCSK9 impairs liver tumor development in vivo. CAM model: Huh6 cells were grafted on the chicken CAM. Tumor growth was monitored on fixed tissues at day 7 after taking the photographs of tumors. The number of CAMs with tumor presenting (labeled with red corner) or not bleeding in CTR versus shPCSK9 is shown in histograms. Two-sided Fisher’s exact test, *: p < 0.05.
Figure 7 Depleting PCSK9 impairs liver tumor development in vivo. CAM model: Huh6 cells were grafted on the chicken CAM. Tumor growth was monitored on fixed tissues at day 7 after taking the photographs of tumors. The number of CAMs with tumor presenting (labeled with red corner) or not bleeding in CTR versus shPCSK9 is shown in histograms. Two-sided Fisher’s exact test, *: p < 0.05.CC BY · PubMed Central

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Authors
Alannan, M., Trézéguet, V., Amoêdo, N. D., Rossignol, R., Mahfouf, W., Rezvani, H. R., Dittrich-Domergue, F., Moreau, P., Lacomme, S., Gontier, E., Grosset, C. F., Badran, B., Fayyad-Kazan, H., & Merched, A. J.
Affiliations
  • Bordeaux Institute of Oncology (BRIC), INSERM U1312, University of Bordeaux, F-33000 Bordeaux, France
  • CELLOMET, Functional Genomics Center (CGFB), INSERM U1211, University of Bordeaux, F-33000 Bordeaux, France
  • Laboratoire de Biogenèse Membranaire, Centre National de la Recherche Scientifique (CNRS), UMR 5200, University of Bordeaux, F-33140 Villenave d’Ornon, France
  • CNRS, INSERM, Bordeaux Imaging Center (BIC), University of Bordeaux, UAR 3420, US 4, F-33000 Bordeaux, France
  • Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath, Beirut, Lebanon
ORCID
Venue
Cancers
Publisher
MDPI AG
Published
2022-12-20
Volume
15
Issue
1
Pages
3
ISSN
2072-6694
DOI
10.3390/cancers15010003
PMC
PMC9817797
Cited by
25
References
0
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • Cassandra contre les Leucémies et Cancers Pédiatriques (OPE-2018-0144, RE-2021-1AD-F, DBI20131228566, N°2020-012)
  • les Récoltes de l’Espoir (OPE-2018-0144, RE-2021-1AD-F, DBI20131228566, N°2020-012)
  • Fondation pour la Recherche Médicale (OPE-2018-0144, RE-2021-1AD-F, DBI20131228566, N°2020-012)
  • PELICAN.resist project and the Région Nouvelle-Aquitaine (OPE-2018-0144, RE-2021-1AD-F, DBI20131228566, N°2020-012)

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