Functional inhibition of heat shock protein 70 by VER-155008 suppresses pleural mesothelioma cell proliferation via an autophagy mechanism.

Abstract

BACKGROUND:

Pleural mesothelioma, a devastating asbestos-associated malignancy, urgently requires a novel effective therapy. Heat shock protein 70 (HSP70), which is synthesized in the cell response to protein damage, is expected to be a new target for antitumor treatment. In addition to its well-known protein refolding function, HSP70 regulates cell proliferation through different pathways, including PI3K/AKT/mTOR, and autophagy in malignant cells. In this study, we attempted to clarify the effects of VER-155008, an HSP70 inhibitor, on pleural mesothelioma.

METHODS:

Human pleural mesothelioma cell lines 211H, H2452 and H28 were cultured with VER-155008, and protein expression, cell proliferation, colony formation, cell cycle, synergistic effect with cisplatin, and autophagy induction were analyzed.

RESULTS:

In mesothelioma cell lines, VER-155008 (5.0 μM or more) inhibited cell growth and colony formation, accompanied by G1 cell cycle arrest. According to western blot analysis, VER-155008 reduced p-AKT expression. However, VER-155008 failed to show a synergistic effect with cisplatin on cell growth. Mesothelioma cells transfected with the novel plasmid pMRX-IP-GFP-LC3-RFP-LC3ΔG, which was developed for the quantitative and statistical estimation of macroautophagy, showed enhanced macroautophagy upon treatment with VER-155008 and gefitinib which is an EGFR-tyrosine kinase inhibitor. In addition, fetal bovine serum deprivation induced macroautophagy was further enhanced by VER-155008.

CONCLUSIONS:

On the basis of these results, functional HSP70 inhibition by VER-155008 suppressed cell growth in pleural mesothelioma cells, accompanied by enhanced macroautophagy. HSP70 inhibition is thus expected to become a new strategy for treating mesothelioma.

KEY POINTS:

Significant findings of the study In pleural mesothelioma cells, inhibition of HSP70 function by VER-155008 suppressed cell proliferation accompanied by induction of autophagy which was synergistically enhanced under the starvation condition, whereas gefitinib, an EGFR-TKI, did not show the same synergistic effect in autophagy. What this study adds The inhibition of HSP70 induced autophagy and suppressed cell proliferation in mesothelioma cells.

• Authors: Kosuke Sakai, Maya Inoue, Shintaro Mikami, Hiroaki Nishimura, Yoshiki Kuwabara, Akitoshi Kojima, Maiko Toda, Yumiko Ogawa-Kobayashi, Satoshi Kikuchi, Yusuke Hirata, Yuriko Mikami-Saito, Hiroyuki Kyoyama, Gaku Moriyama, Michio Shiibashi, Masahiro Seike, Akihiko Gemma, Kazutsugu Uematsu
• Journal: Thoracic cancer (Thorac Cancer) Vol. 12 Issue 4 Pg. 491-503 (02 2021) ISSN: 1759-7714 [Electronic] Singapore
• PMID: 33319489 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

Chemical References

• HSP70 Heat-Shock Proteins
• Purine Nucleosides
• VER 155008

Topics

• Autophagy
• Cell Line, Tumor
• Cell Proliferation
• HSP70 Heat-Shock Proteins (metabolism)
• Humans
• Mesothelioma (drug therapy, pathology)
• Pleural Neoplasms (drug therapy, pathology)
• Purine Nucleosides (pharmacology, therapeutic use)
• Transfection