Resistance to caspase-8 and -9 fragments in a malignant pleural mesothelioma cell line with acquired cisplatin-resistance

Our plain-English summary of Resistance to caspase-8 and -9 fragments in a malignant pleural mesothelioma cell line with acquired cisplatin-resistance, by V. Janson, A. Johansson, K. Grankvist (Cell Death & Disease, 2010).

The study

• Authors: V. Janson, A. Johansson, K. Grankvist
• Journal: Cell Death & Disease
• Published: 2010;1(9):e78
• Cited by: 25 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Apoptotic cysteine-aspartate proteases (caspases) are essential for the progression and execution of apoptosis, and detection of caspase fragmentation or activity is often used as markers of apoptosis. Cisplatin (cis-diamminedichloroplatinum (II)) is a chemotherapeutic drug that is clinically used for the treatment of solid tumours. We compared a cisplatin-resistant pleural malignant mesothelioma cell line (P31res1.2) with its parental cell line (P31) regarding the consequences of in vitro acquired cisplatin-resistance on basal and cisplatin-induced (equitoxic and equiapoptotic cisplatin concentrations) caspase-3, -8 and -9 fragmentation and proteolytic activity. Acquisition of cisplatin-resistance resulted in basal fragmentation of caspase-8 and -9 without a concomitant increase in proteolytic activity, and there was an increased basal caspase-3/7 activity. Similarly, cisplatin-resistant non-small-cell lung cancer cells, H1299res, had increased caspase-3 and -9 content compared with the parental H1299 cells. In P31 cells, cisplatin exposure resulted in caspase-9-mediated caspase-3/7 activation, but in P31res1.2 cells the cisplatin-induced caspase-3/7 activation occurred before caspase-8 or -9 activation. We therefore concluded that in vitro acquisition of cisplatin-resistance rendered P31res1.2 cells resistant to caspase-8 and caspase-9 fragments and that cisplatin-induced, initiator-caspase independent caspase-3/7 activation was necessary to overcome this resistance. Finally, the results demonstrated that detection of cleaved caspase fragments alone might be insufficient as a marker of caspase activity and ensuing apoptosis induction.

In plain English

This was a laboratory study of cancer cells grown in dishes. It did not study asbestos exposure or patients. The authors compared a human malignant pleural mesothelioma cell line (P31) with a sub-line that had been made about four times more resistant to the chemotherapy drug cisplatin (P31res1.2). They measured caspases, which are enzymes involved in programmed cell death, before and after cisplatin exposure lasting 30 minutes to 24 hours. Without any drug, the resistant cells had higher caspase-3/7 activity. They also had more broken-up (fragmented) caspase-8 and -9, but no higher caspase-8 or -9 activity. After cisplatin, caspase-3/7 activity rose at 6 hours in the resistant cells but not in the parental cells. Caspase-8 and -9 activity rose significantly in both lines only after 24 hours. Resistant non-small-cell lung cancer cells (H1299res) also had more caspase-9 and more caspase-9 fragments than their parental cells. The authors concluded that the resistant mesothelioma cells had become resistant to caspase-8 and -9 fragments. They also concluded that detecting caspase fragments alone is not enough to show caspase activity or cell death.

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, with measurements at several time points
• Who was studied: A human malignant mesothelioma cell line of pleural origin (P31) and its cisplatin-resistant sub-line (P31res1.2). For comparison, a non-small-cell lung cancer cell line (H1299) and its cisplatin-resistant sub-line (H1299res) were also studied under control conditions. No human subjects were involved.
• Exposure: Cisplatin, a chemotherapy drug, at concentrations printed as 10 mg/l for P31 cells and 40 mg/l for P31res1.2 cells. These were described as equally toxic and equally apoptosis-inducing for the two lines. Exposures lasted 0.5, 2, 6 or 24 hours. No asbestos or fiber exposure was studied.
• Main results:
  • Without cisplatin, the resistant P31res1.2 cells had higher caspase-3/7 activity than the parental P31 cells.
  • Western blotting detected no caspase-3 fragments in either cell line without cisplatin.
  • A 6-hour cisplatin exposure increased caspase-3/7 activity in P31res1.2 cells but caused no change in P31 cells. After 24 hours, caspase-3/7 activity and PARP fragmentation were similar in the two lines.
  • Without cisplatin, P31res1.2 cells had more caspase-8 and -9 fragments than P31 cells, but no higher caspase-8 or -9 activity.
  • Caspase-8 and -9 activities rose significantly in both mesothelioma cell lines only after 24 hours of cisplatin exposure.
  • Compared with the parental H1299 lung cancer cells, the resistant H1299res cells had more caspase-9 and more caspase-9 fragments.
  • In a protein array, the levels of cIAP-2, survivin and XIAP (proteins that inhibit cell death) were higher in P31res1.2 cells.
  • A 24-hour cisplatin exposure reduced full-length XIAP and XIAP fragmentation in both mesothelioma cell lines.
• The authors' conclusion: The authors concluded that acquiring cisplatin resistance in the lab made P31res1.2 cells resistant to caspase-8 and caspase-9 fragments. They concluded that cisplatin-induced caspase-3/7 activation was needed to overcome this resistance. They also concluded that detecting caspase fragments alone is insufficient as a marker of caspase activity and of apoptosis induction.
• Limitations the authors state:
  • The authors stated that further studies are needed to fully characterize caspase activity in the H1299 and H1299res cells.
  • The authors stated it is not clear whether the XIAP fragments still inhibit caspase-9 or caspase-3.
  • The authors stated that the proposed mechanism inhibiting caspase-8 activity remains to be verified.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Cisplatin, Apoptosis, Mesothelioma, Lung Cancer.

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• Impact of metallothionein-knockdown on cisplatin resistance in malignant pleural mesothelioma — S. Borchert, P.M. Suckrau, et al. (2020)
• Unsymmetric Cisplatin-Based Pt(IV) Conjugates Containing a PARP-1 Inhibitor Pharmacophore Tested on Malignant Pleural Mesothelioma Cell Lines — E. Gabano, G. Pinton, et al. (2021)
• Loss of C/EBP-β LIP drives cisplatin resistance in malignant pleural mesothelioma — J. Kopecka, I.C. Salaroglio, et al. (2018)

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