TY - JOUR
T1 - Caspase-3-Induced Activation of SREBP2 Drives Drug Resistance via Promotion of Cholesterol Biosynthesis in Hepatocellular Carcinoma
AU - Mok, Etienne Ho Kit
AU - Leung, Carmen Oi Ning
AU - Zhou, Lei
AU - Lei, Martina Mang Leng
AU - Leung, Hoi Wing
AU - Tong, Man
AU - Wong, Tin Lok
AU - Lau, Eunice Yuen Ting
AU - Ng, Irene Oi Lin
AU - Ding, Jin
AU - Yun, Jing Ping
AU - Yu, Jun
AU - Zhu, Hui Lian
AU - Lin, Chi Ho
AU - Lindholm, Dan
AU - Leung, Kit Sum
AU - Cybulski, Jonathan D.
AU - Baker, David M.
AU - Ma, Stephanie
AU - Lee, Terence Kin Wah
N1 - Funding Information:
This study was supported by the RGC General Research Fund (15104119 to T.K. Lee), Collaborative Research Fund (C7026–18G), (C7050–18EF to SIRMS), Research Impact Fund (R5050–18F), and the Theme-based Research Scheme project (T12–704/16-R to T.K. Lee, S. Ma, and I.O.L. Ng). The authors thank the University Research Facility in Life Sciences at Hong Kong Polytechnic University for providing and maintaining the equipment and technical support needed for flow cytometry and imaging work as well as the Centralized Animal Facility at Hong Kong Polytechnic University and the Laboratory Animal Unit at University of Hong Kong for supporting our animal studies. The authors thank Dr. Xin Chen (University of California, San Francisco) for sharing of plasmids used for hydrodynamic tail vein injection. They also thank Centre for PanorOmic Sciences for providing RNA sequencing service and Department of Pathology at University of Hong Kong for frozen tissue sectioning service.
Funding Information:
This study was supported by the RGC General Research Fund (15104119 to T.K. Lee), Collaborative Research Fund (C7026-18G), (C7050-18EF to SIRMS), Research Impact Fund (R5050-18F), and the Theme-based Research Scheme project (T12-704/16-R to T.K. Lee, S. Ma, and I.O.L. Ng). The authors thank the University Research Facility in Life Sciences at Hong Kong Polytechnic University for providing and maintaining the equipment and technical support needed for flow cytometry and imaging work as well as the Centralized Animal Facility at Hong Kong Polytechnic University and the Laboratory Animal Unit at University of Hong Kong for supporting our animal studies. The authors thank Dr. Xin Chen (University of California, San Francisco) for sharing of plasmids used for hydrodynamic tail vein injection. They also thank Centre for PanorOmic Sciences for providing RNA sequencing service and Department of Pathology at University of Hong Kong for frozen tissue sectioning service.
Publisher Copyright:
© 2022 American Association for Cancer Research.
PY - 2022/9/1
Y1 - 2022/9/1
N2 - 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+ stem cells and CD133- 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 HCCcells 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.
AB - 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+ stem cells and CD133- 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 HCCcells 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.
UR - http://www.scopus.com/inward/record.url?scp=85137138532&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-21-2934
DO - 10.1158/0008-5472.CAN-21-2934
M3 - Journal article
C2 - 35767704
AN - SCOPUS:85137138532
SN - 0008-5472
VL - 82
SP - 3102
EP - 3115
JO - Cancer Research
JF - Cancer Research
IS - 17
ER -