Survivin is highly expressed and promotes cell survival in malignant peritoneal mesothelioma

Our plain-English summary of Survivin is highly expressed and promotes cell survival in malignant peritoneal mesothelioma, by N. Zaffaroni, A. Costa, M. Pennati, et al (Cellular Oncology, 2007).

The study

• Authors: N. Zaffaroni, A. Costa, M. Pennati, C. De Marco, E. Affini, M. Madeo, R. Erdas, A. Cabras, S. Kusamura, D. Baratti, M. Deraco, M.G. Daidone
• Journal: Cellular Oncology
• Published: 2007;29(6):453-66
• Cited by: 57 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: The biology of malignant peritoneal mesothelioma (MPM) is largely unknown. In the present study, we assessed the expression of survivin and other members of the inhibitors of apoptosis proteins (IAP) family (IAP-1, IAP-2 and X-IAP) in a series of 32 MPM surgical specimens and investigated the effects of survivin knockdown in an established MPM cell line.

Methods: Expression of different IAPs was measured by immunohistochemistry. MPM cells were transfected with a small-interfering RNA (siRNA) targeting survivin mRNA and analyzed for survivin expression, growth rate, and ability to undergo spontaneous and drug (cisplatin, doxorubicin)-induced apoptosis.

Results: Survivin expression was observed in 29 (91%) surgical MPM specimens, whereas the positivity rate for the other IAPs ranged from 69% to 100%. Transfection of MPM cells with the survivin siRNA induced a marked inhibition of survivin protein expression, a time-dependent decline in cell growth and an enhanced rate of spontaneous and drug-induced apoptosis, with a concomitant increase in the catalytic activity of caspase-9.

Conclusion: Our results show for the first time that survivin, as well as other IAPs, is largely expressed in clinical MPMs and suggest that strategies aimed at down-regulating survivin may provide a novel approach for the treatment of the malignancy.

In plain English

This laboratory study from Milan, Italy, examined survivin and related proteins that help cells avoid programmed cell death (apoptosis) in malignant peritoneal mesothelioma. The article does not discuss asbestos. The authors stained tumor samples from 32 patients (29 malignant, 3 borderline subtype), diagnosed 1996 to 2004 and treated with surgery plus heated abdominal chemotherapy. They also stained 7 normal peritoneum samples. They reported survivin in 90.6% of tumors and in none of the normal samples. The authors observed no association between these protein levels and survival in these patients. In a peritoneal mesothelioma cell line (STO), blocking survivin with a small interfering RNA lowered survivin protein by around 80% at 48 and 72 hours. It cut cell growth by around 80% at 96 hours. It also raised apoptosis to 38.5% of cells at 96 hours, versus under 3% in control cells. Blocking survivin also increased cell death after cisplatin or doxorubicin. The authors concluded this could provide a basis for combined therapies including survivin inhibitors. They said a larger case series with longer follow-up is needed and selection bias cannot be excluded.

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: immunohistochemistry (tissue staining) of archived surgical tumor specimens, plus cell-culture experiments in which survivin was blocked in a peritoneal mesothelioma cell line
• Who was studied: 32 patients with peritoneal tumors: 29 with malignant peritoneal mesothelioma and 3 with a borderline peritoneal histologic subtype. There were 21 women and 11 men, with a median age of 52 (range 29–73). They were diagnosed at the Istituto Nazionale Tumori, Milan, Italy, between 1996 and 2004, and all were treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. The study also used 7 normal peritoneum specimens and the STO peritoneal mesothelioma cell line.
• Exposure: No asbestos or fiber exposure was studied. The laboratory treatments were a survivin-targeting small interfering RNA (100 nM) or a control siRNA. These were given alone or followed by a 1-hour exposure to cisplatin (7.0 to 70 µM) or doxorubicin (0.03 to 3.0 µM).
• Main results:
  • Survivin protein was found in 90.6% of the peritoneal mesothelioma specimens.
  • Moderate or high expression was found in 100% of tumors for IAP-2 and IAP-1. It was found in 68.7% (22/32) for X-IAP and in 34.4% (11/32) for the pro-apoptotic protein Smac/DIABLO.
  • In the 7 normal peritoneum specimens, survivin and X-IAP were absent in all. IAP-1 and IAP-2 were found together in 2.
  • Survivin mRNA was found in 11 of the 12 tumor specimens with frozen tissue available (91.6%). These 11 also expressed survivin protein.
  • In the 32 patients, the authors observed no association between expression of the apoptosis-related proteins (survivin, IAP-1, IAP-2, X-IAP, Smac/DIABLO) and survival. There was only a trend toward longer median survival with slowly proliferating tumors (Ki-67 under 10%): 51 versus 27 months.
  • In STO cells, the survivin siRNA reduced survivin protein by around 80% at 48 and 72 hours after transfection, compared with cells exposed only to the transfection reagent. The reduction was around 50% at 96 hours.
  • In STO cells, survivin siRNA reduced cell growth by 40% at 48 hours, rising to around 80% at 96 hours.
  • In STO cells, apoptosis reached 38.5% of cells at 96 hours with survivin siRNA. It stayed under 3% in control-siRNA and reagent-only cells.
  • In STO cells, caspase-9 activity was 2.6-fold (72 hours) and 4.1-fold (96 hours) higher with survivin siRNA than in reagent-only cells.
  • In STO cells given cisplatin, apoptosis was 30.5% to 85.9% of cells with survivin siRNA. It was 1.5% to 36.1% in reagent-only cells (P less than 0.01).
  • In STO cells given doxorubicin, apoptosis was 9.9% to 63.2% of cells with survivin siRNA. It was 1% to 24.5% in control cells (P less than 0.05).
• The authors' conclusion: The authors concluded that survivin levels influence how peritoneal mesothelioma cells respond to cisplatin and doxorubicin in the laboratory. They said this could provide a rational basis for combined therapies that include survivin inhibitors. Because other anti-apoptotic factors are present, they suggested that targeting several such factors at once may be needed.
• Limitations the authors state:
  • A larger case series with longer follow-up is needed to define whether these markers predict patient prognosis.
  • Selection bias in the cases chosen for the study cannot be excluded.

Topics

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

Medical terms in this study, explained in our Lexicon: Peritoneal Mesothelioma, Apoptosis, Immunohistochemistry, Cisplatin, Doxorubicin.

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• Preclinical development of HIvax: Human survivin highly immunogenic vaccines — P.R. Hoffmann, M. Panigada, et al. (2015)
• Diffuse malignant peritoneal mesothelioma: systematic review of clinical management and biological research — D. Baratti, S. Kusamura, et al. (2011)
• Inhibitor of apoptosis protein-1 promotes tumor cell survival in mesothelioma — G.J. Gordon, K. Appasani, et al. (2002)
• Overexpression of Numb suppresses tumor cell growth and enhances sensitivity to cisplatin in epithelioid malignant pleural mesothelioma — Y. Kang, M. Ding, et al. (2013)

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