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.