Curcumin and mesothelioma

Low PIAS3 Expression in Malignant Mesothelioma Is Associated with Increased STAT3 Activation and Poor Patient Survival

1. Snehal Dabir1, 
2. Amy Kluge1, 
3. Adam Kresak2, 
4. Michael Yang2, 
5. Pingfu Fu3,
6. Bernd Groner4, 
7. Gary Wildey1, and 
8. Afshin Dowlati1,*

+Author Affiliations

1. ¹Division of Hematology and Oncology, Case Comprehensive Cancer Center and University Hospitals Case Medical Center, Cleveland, Ohio.
2. ²Division of Pathology, Case Comprehensive Cancer Center and University Hospitals Case Medical Center, Cleveland, Ohio.
3. ³Division of Biostatistics, Case Comprehensive Cancer Center and University Hospitals Case Medical Center, Cleveland, Ohio.
4. ⁴Institute for Biomedical Research, Georg-Speyer-Haus, Frankfurt, Germany.

1. ↵*Corresponding Author:
   Afshin Dowlati, Department of Medicine, Division of Hematology and Oncology, University Hospitals Case Medical Center, 11100 Euclid Avenue, Mail Stop LKS 5079, Cleveland, OH 44106. Phone: 216-286-6741; Fax: 216-844-5234; E-mail:afshin.dowlati@case.edu

Abstract

Purpose: Deregulation of STAT3 activation is a hallmark of many cancer cells, and the underlying mechanisms are subject to intense investigation. We examined the extent of PIAS3 expression in mesothelioma cells and human tumor samples and determined the functional effects of PIAS3 expression on STAT3 signaling.

Experimental design: We evaluated the expression of PIAS3 in mesothelioma tumors from patients and correlated the expression levels with the course of the disease. We also measured the effects of enhanced PIAS3 activity on STAT3 signaling, cellular growth, and viability in cultured mesothelioma cells.

Results: Gene expression databases revealed that mesotheliomas have the lowest levels of PIAS3 transcripts among solid tumors. PIAS3 expression in human mesothelioma tumors is significantly correlated with overall survival intervals (P = 0.058). The high expression of PIAS3 is predictive of a favorable prognosis and decreases the probability of death within one year after diagnosis by 44%. PIAS3 expression is functionally linked to STAT3 activation in mesothelioma cell lines. STAT3 downregulation with siRNA or enhanced expression of PIAS3 both inhibited mesothelioma cell growth and induced apoptosis. Mesothelioma cells are sensitive to curcumin and respond by the induction of PIAS3. Corroborative evidence has been obtained from STAT3 inhibition experiments. Exposure of the cells to a peptide derived from the PIAS3 protein that interferes with STAT3 function resulted in apoptosis induction and the inhibition of cell growth.

Conclusion: These results suggest that PIAS3 protein expression impacts survival in patients with mesothelioma and that PIAS3 activation could become a therapeutic strategy. Clin Cancer Res; 20(19); 1–9. ©2014 AACR.

Curcumin: A Double Hit on Malignant Mesothelioma

1. Jill M. Miller, 
2. Joyce K. Thompson, 
3. Maximilian B. MacPherson, 
4. Stacie L. Beuschel,
5. Catherine M. Westbom, 
6. Mutlay Sayan, and 
7. Arti Shukla

+Author Affiliations

1. Authors' Affiliation: Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont

1. Corresponding Author:
   Arti Shukla, Department of Pathology, University of Vermont College of Medicine, 89 Beaumont Avenue, HSRF 216, Burlington, VT 05405-0068. Phone: 802-656-8253; Fax: 802-656-8892; E-mail: arti.shukla@uvm.edu

Abstract

Inflammation is a key mediator in the development of malignant mesothelioma, which has a dismal prognosis and poor therapeutic strategies. Curcumin, a naturally occurring polyphenol in turmeric, has been shown to possess anticarcinogenic properties through its anti-inflammatory effects. Inflammasomes, a component of inflammation, control the activation of caspase-1 leading to pyroptosis and processing of proinflammatory cytokines, interleukin (IL)-1β and IL-18. In the present study, we investigate the role of curcumin in pyroptotic cell death of malignant mesothelioma cells. Using in vitro models with mouse and human malignant mesothelioma cells, curcumin is shown to induce pyroptosis through activation of caspase-1 and increased release of high-mobility group box 1 (HMGB1) without processing of IL-1β and IL-18. Absence of IL-1β processing in response to curcumin-mediated caspase-1 activation is attributed to blockade of pro-IL-1β priming through inhibition of the NF-κB pathway. Furthermore, curcumin's cytotoxicity in malignant mesothelioma cells is demonstrated to be dependent on pyroptosis as inhibition of caspase-1 resulted in protection against curcumin-induced cell death. We also demonstrate that curcumin-mediated caspase-1 activation is oxidant dependent by using N-acetyl-L-cysteine (NAC) to inhibit pyroptosis. PCR array analysis using the human inflammasome template revealed that curcumin significantly downregulated levels of inflammasome-related gene expression involved in inflammation, e.g., NF-κB, toll-like receptors (TLR), and IL-1β. Our data indicate that curcumin has a double effect on malignant mesothelioma cells through induction of pyroptosis while subsequently protecting against inflammation. Cancer Prev Res; 7(3); 330–40. ©2014 AACR.