ORCID Profile
0000-0003-0682-322X
Current Organisation
Hong Kong Polytechnic University
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Publisher: Impact Journals, LLC
Date: 17-12-2016
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6513947.V1
Abstract: Abstract Accumulating evidence has demonstrated that drug resistance can be acquired in cancer through the repopulation of tumors by cancer stem cell (CSC) expansion. Here, we investigated mechanisms driving resistance and CSC repopulation in hepatocellular carcinoma (HCC) as a cancer model using two drug-resistant, patient-derived tumor xenografts that mimicked the development of acquired resistance to sorafenib or lenvatinib treatment observed in patients with HCC. RNA sequencing analysis revealed that cholesterol biosynthesis was most commonly enriched in the drug-resistant xenografts. Comparison of the genetic profiles of CD133 sup + /sup stem cells and CD133 sup − /sup bulk cells from liver regeneration and HCC mouse models showed that the cholesterol pathway was preferentially upregulated in liver CSCs compared with normal liver stem cells. Consistently, SREBP2-mediated cholesterol biosynthesis was crucial for the augmentation of liver CSCs, and loss of SREBP2 conferred sensitivity to tyrosine kinase inhibitors, suggesting a role in regulation of acquired drug resistance in HCC. Similarly, exogenous cholesterol-treated HCC cells showed enhanced cancer stemness abilities and drug resistance. Mechanistically, caspase-3 (CASP3) mediated cleavage of SREBP2 from the endoplasmic reticulum to promote cholesterol biosynthesis, which consequently caused resistance to sorafenib/lenvatinib treatment by driving activation of the sonic hedgehog signaling pathway. Simvastatin, an FDA-approved cholesterol-lowering drug, not only suppressed HCC tumor growth but also sensitized HCC cells to sorafenib. These findings demonstrate that CSC populations in HCC expand via CASP3-dependent, SREBP2-mediated cholesterol biosynthesis in response to tyrosine kinase inhibitor therapy and that targeting cholesterol biosynthesis can overcome acquired drug resistance. Significance: This study finds that cholesterol biosynthesis supports the expansion of cancer stem cell populations to drive resistance to tyrosine kinase inhibitor therapy in hepatocellular carcinoma, identifying potential therapeutic approaches for improving cancer treatment. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6512922.V1
Abstract: Abstract The survival benefit derived from sorafenib treatment for patients with hepatocellular carcinoma (HCC) is modest due to acquired resistance. Targeting cancer stem cells (CSC) is a possible way to reverse drug resistance, however, inhibitors that specifically target liver CSCs are limited. In this study, we established two sorafenib-resistant, patient-derived tumor xenografts (PDX) that mimicked development of acquired resistance to sorafenib in patients with HCC. RNA-sequencing analysis of sorafenib-resistant PDXs and their corresponding mock controls identified EPH receptor B2 (EPHB2) as the most significantly upregulated kinase. EPHB2 expression increased stepwise from normal liver tissue to fibrotic liver tissue to HCC tissue and correlated with poor prognosis. Endogenous EPHB2 knockout showed attenuation of tumor development in mice. EPHB2 regulated the traits of liver CSCs similarly, sorted EPHB2High HCC cells were endowed with enhanced CSC properties when compared with their EPHB2-Low counterparts. Mechanistically, EPHB2 regulated cancer stemness and drug resistance by driving the SRC/AKT/GSK3β/β-catenin signaling cascade, and EPHB2 expression was regulated by TCF1 via promoter activation, forming a positive Wnt/β-catenin feedback loop. Intravenous administration of rAAV-8-shEPHB2 suppressed HCC tumor growth and significantly sensitized HCC cells to sorafenib in an NRAS/AKT-driven HCC immunocompetent mouse model. Targeting a positive feedback loop involving the EPHB2/β-catenin axis may be a possible therapeutic strategy to combat acquired drug resistance in HCC. Significance: This study identifies a EPHB2/β-catenin/TCF1 positive feedback loop that augments cancer stemness and sorafenib resistance in HCC, revealing a targetable axis to combat acquired drug resistance in HCC. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428138
Abstract: Supplementary Information
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-01-2020
DOI: 10.1002/HEP.30923
Abstract: Most tumor cells use aerobic glycolysis (the Warburg effect) to support anabolic growth and promote tumorigenicity and drug resistance. Intriguingly, the molecular mechanisms underlying this phenomenon are not well understood. In this work, using gain‐of‐function and loss‐of‐function in vitro studies in patient‐derived organoid and cell cultures as well as in vivo positron emission tomography–magnetic resonance imaging animal models, we showed that protein arginine N‐methyltransferase 6 (PRMT6) regulates aerobic glycolysis in human hepatocellular carcinoma (HCC) through nuclear relocalization of pyruvate kinase M2 isoform (PKM2), a key regulator of the Warburg effect. We found PRMT6 to methylate CRAF at arginine 100, interfering with its RAS/RAF binding potential, and therefore altering extracellular signal–regulated kinase (ERK)‐mediated PKM2 translocation into the nucleus. This altered PRMT6‐ERK‐PKM2 signaling axis was further confirmed in both a HCC mouse model with endogenous knockout of PRMT6 as well as in HCC clinical s les. We also identified PRMT6 as a target of hypoxia through the transcriptional repressor element 1‐silencing transcription factor, linking PRMT6 with hypoxia in driving glycolytic events. Finally, we showed as a proof of concept the therapeutic potential of using 2‐deoxyglucose, a glycolysis inhibitor, to reverse tumorigenicity and sorafenib resistance mediated by PRMT6 deficiency in HCC. Our findings indicate that the PRMT6‐ERK‐PKM2 regulatory axis is an important determinant of the Warburg effect in tumor cells, and provide a mechanistic link among tumorigenicity, sorafenib resistance, and glucose metabolism.
Publisher: Springer Science and Business Media LLC
Date: 16-08-2014
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431593.V1
Abstract: Supplementary Data from Caspase-3–Induced Activation of SREBP2 Drives Drug Resistance via Promotion of Cholesterol Biosynthesis in Hepatocellular Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428138.V1
Abstract: Supplementary Information
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22431593
Abstract: Supplementary Data from Caspase-3–Induced Activation of SREBP2 Drives Drug Resistance via Promotion of Cholesterol Biosynthesis in Hepatocellular Carcinoma
Publisher: Wiley
Date: 27-10-2017
DOI: 10.1002/PATH.4976
Publisher: American Association for Cancer Research (AACR)
Date: 29-06-2022
DOI: 10.1158/0008-5472.CAN-21-2934
Abstract: This study finds that cholesterol biosynthesis supports the expansion of cancer stem cell populations to drive resistance to tyrosine kinase inhibitor therapy in hepatocellular carcinoma, identifying potential therapeutic approaches for improving cancer treatment.
Publisher: Springer Science and Business Media LLC
Date: 19-08-2023
DOI: 10.1038/S41420-023-01600-0
Abstract: Autophagy is a lysosome-dependent bulk degradation process essential for cell viability but excessive autophagy leads to a unique form of cell death termed autosis. Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with notable defect in its autophagy process. In previous studies, we developed stapled peptides that specifically targeted the essential autophagy protein Beclin 1 to induce autophagy and promote endolysosomal trafficking. Here we show that one lead peptide Tat-SP4 induced mild increase of autophagy in TNBC cells but showed potent anti-proliferative effect that could not be rescued by inhibitors of programmed cell death pathways. The cell death induced by Tat-SP4 showed typical features of autosis including sustained adherence to the substrate surface, rupture of plasma membrane and effective rescue by digoxin, a cardioglycoside that blocks the Na + /K + ATPase. Tat-SP4 also induced prominent mitochondria dysfunction including loss of mitochondria membrane potential, elevated mitochondria reactive oxygen species and reduced oxidative phosphorylation. The anti-proliferative effect of Tat-SP4 was confirmed in a TNBC xenograft model. Our study uncovers three notable aspects of autosis. Firstly, autosis can be triggered by moderate increase in autophagy if such increase exceeds the endogenous capacity of the host cells. Secondly, mitochondria may play an essential role in autosis with dysregulated autophagy leading to mitochondria dysfunction to trigger autosis. Lastly, intrinsic autophagy deficiency and quiescent mitochondria bioenergetic profile likely render TNBC cells particularly susceptible to autosis. Our designed peptides like Tat-SP4 may serve as potential therapeutic candidates against TNBC by targeting this vulnerability.
Publisher: American Association for Cancer Research (AACR)
Date: 26-04-2021
DOI: 10.1158/0008-5472.CAN-21-0184
Abstract: This study identifies a EPHB2/β-catenin/TCF1 positive feedback loop that augments cancer stemness and sorafenib resistance in HCC, revealing a targetable axis to combat acquired drug resistance in HCC.
Publisher: Impact Journals, LLC
Date: 29-04-2016
No related grants have been discovered for Kin Wah Lee.