Autophagy inhibition switches low-dose camptothecin-induced premature senescence to apoptosis in human colorectal cancer cells

Jian-wei Zhang; Shan-shan Zhang; Jian-rui Song; Kai Sun; Chen Zong; Qiu-dong Zhao; Wen-ting Liu; Rong Li; Meng-chao Wu; Li-xin Wei

doi:10.1016/j.bcp.2014.05.009

Autophagy inhibition switches low-dose camptothecin-induced premature senescence to apoptosis in human colorectal cancer cells

Biochem Pharmacol. 2014 Aug 1;90(3):265-75. doi: 10.1016/j.bcp.2014.05.009. Epub 2014 May 22.

Authors

Affiliations

¹ Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
² Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China; Departments of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, United States.
³ Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China; Medical Sciences Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁴ Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China. Electronic address: weilixin_smmu@163.com.

PMID: 24858802
DOI: 10.1016/j.bcp.2014.05.009

Abstract

Recently, several studies indicated that senescent tumor cells are resistant to apoptosis in chemotherapy. They may return to cell cycle, thus act as stumbling blocks in anticancer treatments. In the present study, we found that, in human colorectal cancer cells, low-dose camptothecin (CPT) simultaneously induced autophagy and premature senescence through AMPK-TSC2-mTOR pathway and ATM-Chk2-p53-p21 pathway respectively. What's important is the suppression of autophagy substantially increased apoptosis and greatly attenuated senescence possibly by blocking p53/p21 pathway, which suggests that autophagy plays an indispensable role in sustaining cell senescence caused by low-dose CPT. The combination of low-dose CPT and autophagy inhibitor, a way to lead senescent cells to die, would be potentially valuable in cancer therapy.

Keywords: Apoptosis; Autophagy; DNA damage response; Human colorectal cancer cells; Low-dose chemotherapy; Senescence.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / metabolism
Adenine / analogs & derivatives*
Adenine / pharmacology
Antineoplastic Agents / agonists
Antineoplastic Agents / antagonists & inhibitors
Antineoplastic Agents / pharmacology
Apoptosis / drug effects*
Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors
Ataxia Telangiectasia Mutated Proteins / chemistry
Ataxia Telangiectasia Mutated Proteins / metabolism
Autophagy / drug effects*
Camptothecin / agonists*
Camptothecin / antagonists & inhibitors
Camptothecin / pharmacology
Cell Line, Tumor
Cellular Senescence / drug effects*
Chloroquine / pharmacology*
Class III Phosphatidylinositol 3-Kinases / pharmacology
Colorectal Neoplasms / drug therapy*
Colorectal Neoplasms / metabolism
Colorectal Neoplasms / pathology
Drug Resistance, Neoplasm / drug effects
Enzyme Inhibitors / pharmacology
Humans
Lysosomes / drug effects
Neoplasm Proteins / agonists
Neoplasm Proteins / antagonists & inhibitors
Neoplasm Proteins / metabolism
Osmolar Concentration
Signal Transduction / drug effects
Tumor Suppressor Protein p53 / antagonists & inhibitors
Tumor Suppressor Protein p53 / metabolism

Substances

Antineoplastic Agents
Enzyme Inhibitors
Neoplasm Proteins
TP53 protein, human
Tumor Suppressor Protein p53
3-methyladenine
Chloroquine
Class III Phosphatidylinositol 3-Kinases
ATM protein, human
Ataxia Telangiectasia Mutated Proteins
AMP-Activated Protein Kinases
Adenine
Camptothecin