Bortezomib induces protective autophagy through AMP-activated protein kinase activation in cultured pancreatic and colorectal cancer cells.
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.
Department of Gastroenterology, Drum Tower Clinical Medical College of Nanjing Medical University, Zhongshan Road 321, Nanjing, 210008, People's Republic of China.
Han
H
Min
Min
M
Xu
Zhi-Rong
ZR
Chen
Jun-Dong
JD
Zhou
Min
M
Huang
Kai
K
Zheng
Xiao-Ping
XP
Zou
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D001897:Boronic Acids / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000069286:Bortezomib; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D009363:Neoplasm Proteins / Q000819:agonists / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D061988:Proteasome Inhibitors / Q000819:agonists / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors; D011719:Pyrazines / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering
D000970:Antineoplastic Agents; D001897:Boronic Acids; D009363:Neoplasm Proteins; D061988:Proteasome Inhibitors; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D034741:RNA, Small Interfering; C025946:3-methyladenine; D000069286:Bortezomib; D002738:Chloroquine; D055372:AMP-Activated Protein Kinases; D000225:Adenine