Targeting Mcl-1 inhibits survival and self-renewal of hepatocellular cancer stem-like cells

Huapeng Zhang; Gongquan Li; Guanghui Chen; Yi Zhang; Jie Pan; Hongwei Tang; Jie Li; Wenzhi Guo; Shuijun Zhang

doi:10.1016/j.clinre.2018.11.004

Targeting Mcl-1 inhibits survival and self-renewal of hepatocellular cancer stem-like cells

Clin Res Hepatol Gastroenterol. 2019 Jun;43(3):292-300. doi: 10.1016/j.clinre.2018.11.004. Epub 2018 Dec 5.

Authors

Huapeng Zhang¹, Gongquan Li¹, Guanghui Chen¹, Yi Zhang², Jie Pan¹, Hongwei Tang¹, Jie Li¹, Wenzhi Guo¹, Shuijun Zhang³

Affiliations

¹ Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China; Open and Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China; Zhengzhou Key Laboratory of Hepatobiliary and Pancreatic Diseases and Organ Transplantation, Zhengzhou, Henan, PR China; Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, Henan, PR China.
² Open and Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China; Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China.
³ Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China; Open and Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China; Zhengzhou Key Laboratory of Hepatobiliary and Pancreatic Diseases and Organ Transplantation, Zhengzhou, Henan, PR China; Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, Henan, PR China. Electronic address: zhangshuijun@hotmail.com.

PMID: 30528319
DOI: 10.1016/j.clinre.2018.11.004

Abstract

Myeloid cell leukemia-1 (Mcl-1) is highly expressed in tumor tissues and cells of hepatocellular carcinoma (HCC), yet the role of Mcl-1 in cancer stem-like cells (CSLCs) remains largely unclear. Herein, we showed that knockdown of Mcl-1 significantly inhibited HCC cells to form spheres under ultra-low attachment condition in serum-free medium, and also attenuated clone formation. Inhibition of Mcl-1 by specific inhibitors S63845 or A-1210477 hindered secondary sphere formation, triggered apoptosis signaling and reduced the level of stem cell transcription factor Nanog, Sox2 and KLF4 in HCC spheroids cells. This study suggests that Mcl-1 is an essential factor for the survival and self-renewal of HCC CSLCs.

Keywords: Cancer stem-like cells; Hepatocellular carcinoma; Mcl-1; Mcl-1 inhibitor.

MeSH terms

Antineoplastic Agents / pharmacology*
Apoptosis
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology*
Cell Line, Tumor
Cell Self Renewal / drug effects*
Cell Survival / drug effects
Humans
Indoles / pharmacology
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors / drug effects
Kruppel-Like Transcription Factors / metabolism
Liver Neoplasms / metabolism
Liver Neoplasms / pathology*
Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors*
Myeloid Cell Leukemia Sequence 1 Protein / metabolism
Nanog Homeobox Protein / drug effects
Nanog Homeobox Protein / metabolism
Neoplastic Stem Cells / drug effects*
Pyrimidines / pharmacology
SOXB1 Transcription Factors / drug effects
SOXB1 Transcription Factors / metabolism
Sulfonamides / pharmacology
Thiophenes / pharmacology

Substances

A-1210477
Antineoplastic Agents
Indoles
KLF4 protein, human
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors
Myeloid Cell Leukemia Sequence 1 Protein
Nanog Homeobox Protein
Pyrimidines
S63845
SOX2 protein, human
SOXB1 Transcription Factors
Sulfonamides
Thiophenes