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Cancer Chemotherapy and Pharmacology

, Volume 74, Issue 1, pp 167–176 | Cite as

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

  • Han Min
  • Min Xu
  • Zhi-rong ChenEmail author
  • Jun-dong Zhou
  • Min Huang
  • Kai Zheng
  • Xiao-ping ZouEmail author
Original Article

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.

Keywords

Bortezomib Autophagy AMPK Apoptosis-resistance and chemo-sensitization 

Abbreviation

AMPK

AMP-activated protein kinase

ACC

Acetyl-CoA carboxylase

3-MA

3-Methyladenine

LC3B

Light chain 3B

Notes

Acknowledgments

This research was supported by grants from the National Natural Science Foundation (to Jun-dong Zhou).

Conflict of interest

No conflict of interests was stated.

Supplementary material

280_2014_2451_MOESM1_ESM.docx (388 kb)
Supplementary material 1 (DOCX 388 kb) The effect of bortezomib on JNK activation. PANC-1 and HT-29 cancer cells were treated with vehicle (V, 0.1 % DMSO) or bortezomib (100 nM), and cultured for 12 or 24 h, or treated with H2O2 (200 μM) for 12 h, p-JNK1/2 and JNK1 were tested by Western blots (A and B). Experiments in this figure were repeated three times

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of GastroenterologyDrum Tower Clinical Medical College of Nanjing Medical UniversityNanjingPeople’s Republic of China
  2. 2.Department of GastroenterologyNanjing Medical University Affiliated Suzhou HospitalSuzhouPeople’s Republic of China
  3. 3.Department of GI MedicineWuxi People’s HospitalWuxiPeople’s Republic of China
  4. 4.Tumor LabNanjing Medical University Affiliated Suzhou HospitalSuzhouPeople’s Republic of China

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