2. Academic Validation
  3. The proton pump inhibitor pantoprazole disrupts protein degradation systems and sensitizes cancer cells to death under various stresses

The proton pump inhibitor pantoprazole disrupts protein degradation systems and sensitizes cancer cells to death under various stresses

  • Cell Death Dis. 2018 May 22;9(6):604. doi: 10.1038/s41419-018-0642-6.
Yu Cao 1 2,  Min Chen 1 2,  Dehua Tang 1 2,  Hongli Yan 3,  Xiwei Ding 1 2,  Fan Zhou 1 2,  Mingming Zhang 1 2,  Guifang Xu 1 2,  Weijie Zhang 4 5,  Shu Zhang 1 2,  Yuzheng Zhuge 1 2,  Lei Wang 6 7,  Xiaoping Zou 8 9
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, Jiangsu Province, China.
  • 2 Jiangsu Clinical Medical Center of Digestive Disease, Nanjing, China.
  • 3 Department of Laboratory Medicine, Changhai Hospital, the Second Military Medical University, Shanghai, China.
  • 4 Department of General Surgery, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, China.
  • 5 Department of General Surgery, Drum Tower Clinical College of Nanjing Medical University, Nanjing, Jiangsu Province, China.
  • 6 Department of Gastroenterology, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, Jiangsu Province, China. [email protected].
  • 7 Jiangsu Clinical Medical Center of Digestive Disease, Nanjing, China. [email protected].
  • 8 Department of Gastroenterology, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, Jiangsu Province, China. [email protected].
  • 9 Jiangsu Clinical Medical Center of Digestive Disease, Nanjing, China. [email protected].
PMID: 29789637 DOI: 10.1038/s41419-018-0642-6
Abstract

Proton Pump inhibitors (PPIs) play a role in antitumor activity, with studies showing specialized impacts of PPIs on Cancer cell Apoptosis, metastasis, and Autophagy. In this study, we demonstrated that pantoprazole (PPI) increased autophagosomes formation and affected autophagic flux depending on the pH conditions. PPI specifically elevated SQSTM1 protein levels by increasing SQSTM1 transcription via NFE2L2 activation independent of the specific effect of PPI on autophagic flux. Via decreasing Proteasome subunits expression, PPI significantly impaired the function of the Proteasome, accompanied by the accumulation of undegraded poly-ubiquitinated proteins. Notably, PPI-induced Autophagy functioned as a downstream response of Proteasome inhibition by PPI, while suppressing protein synthesis abrogated Autophagy. Blocking autophagic flux in neutral pH condition or further impairing Proteasome function with Proteasome inhibitors, significantly aggravated PPI cytotoxicity by worsening protein degradation ability. Interestingly, under conditions of mitochondrial stress, PPI showed significant synergism when combined with Bcl-2 inhibitors. Taken together, these findings provide a new understanding of the impact of PPIs on Cancer cells' biological processes and highlight the potential to develop more efficient and effective combination therapies.

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