Increased sensitivity to apoptosis upon endoplasmic reticulum stress-induced activation of the unfolded protein response in chemotherapy-resistant malignant pleural mesothelioma

Our plain-English summary of Increased sensitivity to apoptosis upon endoplasmic reticulum stress-induced activation of the unfolded protein response in chemotherapy-resistant malignant pleural mesothelioma, by D. Xu, S.Q. Liang, H. Yang, et al (British Journal of Cancer, 2018).

The study

• Authors: D. Xu, S.Q. Liang, H. Yang, U. Lüthi, C. Riether, S. Berezowska, T.M. Marti, S.R.R. Hall, R. Bruggmann, G.J. Kocher, R.A. Schmid, R.W. Peng
• Journal: British Journal of Cancer
• Published: 2018;119(1):65-75
• Cited by: 31 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Standard treatment for advanced malignant pleural mesothelioma (MPM) is a cisplatin/pemetrexed (MTA) regimen; however, this is confronted by drug resistance. Proteotoxic stress in the endoplasmic reticulum (ER) is a hallmark of cancer and some rely on this stress signalling in response to cytotoxic chemotherapeutics. We hypothesise that ER stress and the adaptive unfolded protein response (UPR) play a role in chemotherapy resistance of MPM.

Methods: In vitro three-dimensional (3D) and ex vivo organotypic culture were used to enrich a chemotherapy-resistant population and recapitulate an in vivo MPM microenvironment, respectively. Markers of ER stress, the UPR and apoptosis were assessed at mRNA and protein levels. Cell viability was determined based on acid phosphatase activity.

Results: MPM cells with de novo and/or acquired chemotherapy resistance displayed low ER stress, which rendered the cells hypersensitive to agents that induce ER stress and alter the UPR. Bortezomib, an FDA-approved proteasome inhibitor, selectively impairs chemotherapy-resistant MPM cells by activating the PERK/eIF2α/ATF4-mediated UPR and augmenting apoptosis.

Conclusions: We provide the first evidence for ER stress and the adaptive UPR signalling in chemotherapy resistance of MPM, which suggests that perturbation of the UPR by altering ER stress is a novel strategy to treat chemotherapy-refractory MPM.

In plain English

This laboratory study from Bern, Switzerland, examined malignant pleural mesothelioma (MPM) cells. It did not study asbestos exposure. The authors asked whether a cell stress response, the unfolded protein response, is involved in resistance to standard cisplatin plus pemetrexed chemotherapy. They used MPM cell lines, patient-derived cells, a normal mesothelial cell line, and patient tumours grown in mice and then cultured as tissue slices. MPM cells grown as three-dimensional spheres resisted the chemotherapy better than flat-grown cells, and had lower levels of stress-response genes and proteins. Drugs that induce this stress, including bortezomib, reduced the viability of these resistant cells more than that of flat-grown cells. The ratio of a cell-death marker, cleaved caspase-3, in bortezomib-treated versus control-treated MESO-1 cells was 1.46 in three-dimensional cells and 0.95 in flat-grown cells of the same line. Bortezomib plus chemotherapy caused more cell death in resistant cells than either treatment alone. Using RNA interference to reduce production of the CHOP protein weakened bortezomib's effect. The authors concluded that altering this stress response may be a novel strategy for chemotherapy-resistant MPM. The work used cells and tissue, not patients.

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 study using cell cultures (flat 2D and three-dimensional sphere culture), plus patient tumours grown in mice and then cultured ex vivo as tissue slices
• Who was studied: MPM cell lines (H28, MESO-1, MESO-4, MSTO-211H, JL-1), a normal mesothelial cell line (Met-5A), patient-derived primary MPM cells (BE261T), and xenograft tumours from one MPM patient (BE454) grown in NSG mice. Patient tissue came from surgery at Bern University Hospital, Switzerland.
• Exposure: No asbestos exposure was studied. Cells and tissues were treated with the chemotherapy drugs cisplatin and pemetrexed (MTA), and with the ER stress-inducing agents HA15, thapsigargin and bortezomib. ABT-263 was also tested.
• Main results:
  • MPM cells grown in 3D culture, derived from H28, MESO-1 and MESO-4, showed reduced sensitivity to cisplatin and MTA compared with flat-grown (2D) cells.
  • 3D (chemotherapy-resistant) cells showed significant downregulation of unfolded protein response genes (HSPA5, EIF2AK3, ATF4, DDIT3) compared with 2D cells.
  • In long-term treatment of H28, MESO-1 and MESO-4 cells, cisplatin/MTA inhibited growth for less than 9 days but failed to do so with treatment beyond 9 days, which the authors took as emergence of resistance.
  • HA15 and thapsigargin lowered MESO-1 viability and were more damaging to 3D than to 2D MESO-1 cells.
  • In an apoptosis array of MESO-1 cells, the ratio of cleaved caspase-3 in bortezomib-treated versus DMSO-treated cells was 1.46 in 3D cells and 0.95 in parental 2D cells.
  • In 3D cells, bortezomib increased pro-apoptotic SMAC by 38% and Hsp60 by 24% compared with DMSO. In 2D cells it repressed SMAC and increased Hsp60 by 11%.
  • In chemotherapy-resistant cells, combined bortezomib and cisplatin/MTA triggered significantly greater apoptosis than either treatment alone.
  • Among the cells tested, MESO-4 was the most sensitive to bortezomib and BE261T the most resistant. MESO-4 was intrinsically more resistant to cisplatin/MTA than BE261T.
  • Reducing CHOP expression in MESO-1 cells with RNA interference significantly compromised the inhibitory effect of bortezomib on cell viability.
• The authors' conclusion: The authors concluded that ER stress and the adaptive unfolded protein response play a role in chemotherapy resistance of MPM. They suggested that altering ER stress may be a novel strategy to treat chemotherapy-resistant MPM.
• Limitations the authors state:
  • The authors stated that future studies are needed to clarify the link between bortezomib-induced HIF-1α, apoptosis and chemotherapy response.
  • The authors stated that the nature of chemotherapy-resistant MPM cells, including whether they are equivalent to cancer stem cells, was beyond the scope of this study.

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: Apoptosis, Chemotherapy, Pleural Mesothelioma, Cisplatin, Pemetrexed (Alimta), De Novo.

Related studies

• Asbestos-induced alveolar epithelial cell apoptosis. The role of endoplasmic reticulum stress response — D.W. Kamp, G. Liu, et al. (2013)
• Repression of GADD153/CHOP by NF-kappaB: a possible cellular defense against endoplasmic reticulum stress-induced cell death — S. Nozaki, G.W. Sledge, et al. (2001)
• Asbestos-induced disruption of calcium homeostasis induces endoplasmic reticulum stress in macrophages — A.J. Ryan, J.L. Larson-Casey, et al. (2014)
• Proteasome stress sensitizes malignant pleural mesothelioma cells to bortezomib-induced apoptosis — F. Cerruti, G. Jocollè, et al. (2017)
• Lamellar Inclusions within Hyperplastic Endoplasmic Reticulum in Benign Mesothelial Cells — S. Haefliger, D. Jain, et al. (2020)
• Role of unfolded proteins in lung disease — K.L. Bradley, C.A. Stokes, et al. (2021)

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