Hypoxia Inducible Factor-1α Inhibition in Von Hippel Lindau-mutant Malignant Pleural Mesothelioma Cells

Our plain-English summary of Hypoxia Inducible Factor-1α Inhibition in Von Hippel Lindau-mutant Malignant Pleural Mesothelioma Cells, by T. Shukuya, J. Oyanagi, M. Serizawa, et al (Anticancer Research, 2020).

The study

• Authors: T. Shukuya, J. Oyanagi, M. Serizawa, M. Watanabe, N. Yamamoto, Y. Koh
• Journal: Anticancer Research
• Published: 2020;40(4):1867-1874
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background/aim: Molecular targeted agents have been successfully developed against solid tumors and their use is also being investigated for the treatment of malignant pleural mesothelioma (MPM). We have previously reported von Hippel Lindau (VHL) mutations detected by massive parallel sequencing technology in samples of patients with MPM. Here, we conducted an in vitro study to investigate the therapeutic approaches in VHL-mutant MPM.

Materials And Methods: Three MPM cell lines with or without a VHL mutation were used and the effects of molecular-targeted agents on growth inhibition were evaluated. Based on the characteristics of the molecular targeted agents that exhibited growth inhibitory effect, the effects of knockdown by siRNA were also evaluated.

Results: NCI-H28 MPM cells harboring the VHL L89H mutation were sensitive to YC-1, known as an inhibitor of hypoxia inducible factor (HIF)-1α, and YC-1treatment induced massive apoptosis in a dose-and-time-dependent manner. Knockdown of HIF-1α by siRNA partially inhibited the growth of NCI-H28 cells, suggesting that an additional blockade may be required to completely inhibit growth signaling.

Conclusion: The VHL mutation may predict tumor responses to YC-1, a HIF-1α inhibitor.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

In plain English

This was a laboratory (in vitro) study of three human malignant pleural mesothelioma cell lines grown in culture. No patients were treated, and asbestos exposure was not studied. The authors tested whether cells carrying a mutation in the VHL gene respond to particular targeted drugs. Gene sequencing confirmed a VHL mutation (L89H) in the NCI-H28 cell line but not in the MSTO-211H or NCI-H2052 lines. NCI-H28 cells made high levels of a protein called HIF-1α even at normal oxygen levels. Eleven targeted drugs were tested on NCI-H28 cells. YC-1, described as an HIF-1α inhibitor, slowed their growth at a concentration (IC50 of 337 nM) more than two-fold lower than the other agents. YC-1's significant growth-inhibiting effect, and signs of programmed cell death (apoptosis), were seen only in NCI-H28 cells. Blocking HIF-1α genetically with siRNA also slowed NCI-H28 growth, but less strongly than YC-1. The authors concluded that YC-1 might be a potential treatment for mesothelioma with this VHL mutation. They noted that YC-1 is not a selective HIF-1α inhibitor and called for study in a larger cohort.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) cell-line experiment
• Who was studied: Three human malignant mesothelioma cell lines (MSTO-211H, NCI-H2052 and NCI-H28) bought from ATCC; no human participants
• Exposure: Not asbestos. The cell lines were exposed to molecular-targeted drugs, including YC-1, and to siRNA knockdown of HIF-1α; growth inhibition was measured
• Main results:
  • A VHL mutation changing leucine-89 to histidine (L89H) was confirmed in NCI-H28 cells; the other two cell lines did not show actionable mutations
  • NCI-H28 cells overexpressed HIF-1α even under normal oxygen conditions
  • In NCI-H28 cells, YC-1 inhibited growth at an IC50 of 337 nM, more than two-fold lower than the other agents tested
  • The significant growth-inhibitory effect of YC-1 was seen only in NCI-H28 cells, not in the two VHL wild-type lines
  • YC-1 for 24 hours induced markers of apoptosis (cleavage of caspase 3 and PARP) in NCI-H28 cells in a dose-dependent manner; this was not seen in the other two lines
  • In NCI-H28 cells, YC-1 abolished MET protein expression and MET phosphorylation, but had little effect on GLUT1 and ENO1
  • Knocking down HIF-1α with siRNA significantly inhibited NCI-H28 growth, but less potently than YC-1
• The authors' conclusion: The authors concluded that YC-1 might be a potential therapeutic agent for patients with malignant pleural mesothelioma who have the L89H VHL mutation, and that the VHL mutation might be a biomarker for YC-1 treatment
• Limitations the authors state:
  • YC-1 is not a selective HIF-1α inhibitor and may act on other molecules
  • The authors stated that these genetic alterations need to be studied in a larger cohort

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Hypoxia, Pleural Mesothelioma, Apoptosis.

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