Bortezomib induces protective autophagy through AMP-activated protein kinase activation in cultured pancreatic and colorectal cancer cells

• Published in: Cancer chemotherapy and pharmacology 2014-07, Vol.74 (1), p.167-176
• Main Authors: Min, Han, Xu, Min, Chen, Zhi-rong, Zhou, Jun-dong, Huang, Min, Zheng, Kai, Zou, Xiao-ping
• Format: Article
• Language: English
• Subjects: Adenine - analogs & derivatives; Adenine - pharmacology; AMP-Activated Protein Kinases - antagonists & inhibitors; AMP-Activated Protein Kinases - chemistry; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Antineoplastic agents; Antineoplastic Agents - agonists; Antineoplastic Agents - antagonists & inhibitors; Antineoplastic Agents - pharmacology; Autophagy - drug effects; Biological and medical sciences; Boronic Acids - agonists; Boronic Acids - antagonists & inhibitors; Boronic Acids - pharmacology; Bortezomib; Cancer Research; Cell Survival - drug effects; Cells, Cultured; Chloroquine - pharmacology; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - enzymology; Colorectal Neoplasms - metabolism; Drug Resistance, Neoplasm - drug effects; Drug Synergism; Enzyme Activation - drug effects; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Medicine; Medicine & Public Health; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Proteins - agonists; Neoplasm Proteins - metabolism; Oncology; Original Article; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Proteasome Inhibitors - agonists; Proteasome Inhibitors - chemistry; Proteasome Inhibitors - pharmacology; Protein Kinase Inhibitors; Pyrazines - agonists; Pyrazines - antagonists & inhibitors; Pyrazines - pharmacology; RNA Interference; RNA, Small Interfering; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-014-2451-7

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.