Abstract
Background:
Bortezomib, a selective and potent inhibitor of the proteasome, has demonstrated broad anti-tumor activities in many malignancies. In the current study, we aimed to understand the potential resistance factor of bortezomib in cultured pancreatic and colorectal cancer cells.
Results:
We observed that bortezomib-induced protective autophagy in cultured PANC-1 pancreatic cancer cells and HT-29 colorectal cancer cells. Inhibition of autophagy by 3-methyladenine (3-MA) and chloroquine enhanced bortezomib-induced apoptosis and cytotoxicity in both PANC-1 and HT-29 cells. Activation of AMP-activated protein kinase (AMPK) was required for bortezomib-induced autophagy induction in PANC-1 and HT-29 cells, and AMPK inhibition by its inhibitor compound C (CC) or RNAi-depletion suppressed bortezomib-induced autophagy, while dramatically enhancing cancer cell apoptosis/cytotoxicity. Meanwhile, significant AMPK activation and autophagy induction were observed after bortezomib stimulation in primary cultured pancreatic cancer cells derived from a patient's tumor tissue. Both CC and 3-MA facilitated bortezomib-induced cytotoxicity in primary cultured pancreatic cancer cells.
Conclusions:
In conclusion, our data here suggest that bortezomib induces protective autophagy in pancreatic and colorectal cancer cells through activating AMPK-Ulk1 signalings. AMPK or autophagy inhibitors could be developed as an adjunct or chemo-sensitizer for bortezomib.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinases / antagonists & inhibitors
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AMP-Activated Protein Kinases / chemistry
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AMP-Activated Protein Kinases / genetics
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AMP-Activated Protein Kinases / metabolism*
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Adenine / analogs & derivatives
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Adenine / pharmacology
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Antineoplastic Agents / agonists
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Antineoplastic Agents / antagonists & inhibitors
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Antineoplastic Agents / pharmacology*
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Autophagy / drug effects*
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Boronic Acids / agonists
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Boronic Acids / antagonists & inhibitors
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Boronic Acids / pharmacology*
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Bortezomib
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Cell Survival / drug effects
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Cells, Cultured
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Chloroquine / pharmacology
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Colorectal Neoplasms / drug therapy*
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Colorectal Neoplasms / enzymology
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Colorectal Neoplasms / metabolism
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Drug Resistance, Neoplasm / drug effects
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Drug Synergism
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Enzyme Activation / drug effects
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Humans
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Neoplasm Proteins / agonists
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Neoplasm Proteins / metabolism
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Pancreatic Neoplasms / drug therapy*
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / pathology
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Proteasome Inhibitors / agonists
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Proteasome Inhibitors / chemistry
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Proteasome Inhibitors / pharmacology*
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Protein Kinase Inhibitors
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Pyrazines / agonists
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Pyrazines / antagonists & inhibitors
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Pyrazines / pharmacology*
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RNA Interference
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RNA, Small Interfering
Substances
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Antineoplastic Agents
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Boronic Acids
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Neoplasm Proteins
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Proteasome Inhibitors
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Protein Kinase Inhibitors
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Pyrazines
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RNA, Small Interfering
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3-methyladenine
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Bortezomib
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Chloroquine
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AMP-Activated Protein Kinases
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Adenine