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Alantolactone induces apoptosis and improves chemosensitivity of pancreatic cancer cells by impairment of autophagy-lysosome pathway via targeting TFEB
- Source :
- Toxicology and Applied Pharmacology. 356:159-171
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- The lysosome is emerging as a central regulator of the autophagic process, which plays a critical role in tumor growth and chemoresistance. Alantolactone, which is a natural compound produced by Inula helenium, has been shown to induce apoptosis in numerous cancer types. However, the mechanism by which alantolactone regulates apoptosis is still poorly understood. In this work, we observed that alantolactone caused the accumulation of autophagosomes due to impaired autophagic degradation and substantially inhibited the activity and expression of CTSB/CTSD proteins that when depleted caused lysosomal dysfunction. Furthermore, we found that alantolactone inhibited the proliferation of pancreatic cancer cells in vitro and in vivo and enhanced the chemosensitivity of pancreatic cancer cells to oxaliplatin. In addition, a reduction in TFEB levels was a critical event in the apoptosis and cell death caused by alantolactone. Our data demonstrated that alantolactone, which impaired autophagic degradation, was a pharmacological inhibitor of autophagy in pancreatic cancer cells and markedly enhanced the chemosensitivity of pancreatic cancer cells to oxaliplatin.
- Subjects :
- 0301 basic medicine
Programmed cell death
Antineoplastic Agents
Apoptosis
Toxicology
Lactones
03 medical and health sciences
Cell Line, Tumor
Phagosomes
Lysosome
Pancreatic cancer
Autophagy
medicine
Humans
Sesquiterpenes, Eudesmane
Cell Proliferation
Pharmacology
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Chemistry
Cancer
Drug Synergism
medicine.disease
Antineoplastic Agents, Phytogenic
In vitro
Oxaliplatin
Pancreatic Neoplasms
030104 developmental biology
medicine.anatomical_structure
Cancer research
TFEB
Lysosomes
Signal Transduction
Subjects
Details
- ISSN :
- 0041008X
- Volume :
- 356
- Database :
- OpenAIRE
- Journal :
- Toxicology and Applied Pharmacology
- Accession number :
- edsair.doi.dedup.....0d8e111e88a6a2037bcf492b53744887