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

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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.

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Abbreviations

AMPK:

AMP-activated protein kinase

ACC:

Acetyl-CoA carboxylase

3-MA:

3-Methyladenine

LC3B:

Light chain 3B

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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.

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Authors and Affiliations

  1. Department of Gastroenterology, Drum Tower Clinical Medical College of Nanjing Medical University, Zhongshan Road 321, Nanjing, 210008, People’s Republic of China

    Han Min & Xiao-ping Zou

  2. Department of Gastroenterology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, 215001, People’s Republic of China

    Han Min & Zhi-rong Chen

  3. Department of GI Medicine, Wuxi People’s Hospital, Wuxi, 214000, Jiangsu, People’s Republic of China

    Min Xu

  4. Tumor Lab, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, 215001, People’s Republic of China

    Jun-dong Zhou, Min Huang & Kai Zheng

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  1. Han Min
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  2. Min Xu
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  4. Jun-dong Zhou
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  5. Min Huang
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Correspondence to Zhi-rong Chen or Xiao-ping Zou.

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280_2014_2451_MOESM1_ESM.docx

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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Min, H., Xu, M., Chen, Zr. et al. Bortezomib induces protective autophagy through AMP-activated protein kinase activation in cultured pancreatic and colorectal cancer cells. Cancer Chemother Pharmacol 74, 167–176 (2014). https://doi.org/10.1007/s00280-014-2451-7

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  • DOI: https://doi.org/10.1007/s00280-014-2451-7

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