Adiponectin pathway attenuates malignant mesothelioma cell growth

Our plain-English summary of Adiponectin pathway attenuates malignant mesothelioma cell growth, by K. Niu, M. Asada, T. Okazaki, et al (American Journal of Respiratory Cell and Molecular Biology, 2012).

The study

• Authors: K. Niu, M. Asada, T. Okazaki, S. Yamanda, T. Ebihara, H. Guo, D. Zhang, R. Nagatomi, H. Arai, M. Kohzuki, S. Ebihara
• Journal: American Journal of Respiratory Cell and Molecular Biology
• Published: 2012;46(4):515-23
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma (MM) is caused by exposure to asbestos. Because MM has a latency period, short survival time, and has a poor response to current therapeutic regimes, long-term preventive strategies are required to suppress the advance of pathological states after asbestos exposure. Accumulating evidence suggests that adiponectin plays a crucial role in the regulation of energy metabolism by increasing AMP-activated protein kinase (AMPK) activation. Several studies have indicated that the activation of AMPK decreases cyclooxygenase (COX)-2 expression. Because high COX-2 levels correlated with a worse prognosis and survival rate in MM, we examined whether the adiponectin pathway suppresses MM cell growth through the AMPK/COX-2 pathway. In vivo, dietary fish oil (a potential promoter of adiponectin) decreased the growth rate of MM, which was accompanied by an increase in adiponectin and phospho-AMPK levels, and a decrease in COX-2 level. In vitro, adiponectin significantly impaired the cell proliferation rate of MM cell lines. These effects partly involved induction of growth arrest and apoptosis to MM cells. MM cells expressed both adiponectin receptors 1 and 2 (AdipoR1 and -R2) at mRNA and proteins levels. These receptors were functional, because adiponectin activated AMPK. Adiponectin treatment also significantly down-regulated protein levels of COX-2 and its downstream prostaglandin E(2). Finally, inhibitory analysis of AdipoR1/R2 by small interfering RNA knockdown suggests that adiponectin enhances AMPK activity and impairs the cell proliferation rate of MM cells, mainly via AdipoR1. These findings suggest that the induction or supplementation of adiponectin is an important tactic for developing therapeutic strategies against MM.

In plain English

This laboratory study tested whether adiponectin, a hormone made by fat tissue, slows the growth of malignant mesothelioma cells. It did not study people or asbestos exposure. Two groups of five male immune-deficient (SCID) mice were fed a diet with either 20% corn oil or 20% menhaden fish oil. They were then injected under the skin with human mesothelioma cells (MSTO-211H). After 25 days, tumors in the fish oil group grew more slowly and weighed significantly less, and these mice had higher blood adiponectin. In their tumors, adiponectin and activated AMPK (an energy-sensing enzyme) were 180% and 160% greater, and COX-2 (an enzyme linked to inflammation) was 30% lower, than in the corn oil group. In four human mesothelioma cell lines grown in dishes, adiponectin significantly reduced cell proliferation in a dose-dependent manner and lowered COX-2 and prostaglandin E2. Silencing the receptor AdipoR1 strongly abolished adiponectin's effects on COX-2 and activated AMPK and significantly restored cell proliferation; silencing AdipoR2 did not. The authors concluded that inducing or supplementing adiponectin is an important tactic for developing treatments for mesothelioma.

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: animal experiment (mice implanted with human mesothelioma cells, fed different diets) plus in vitro experiments on human mesothelioma cell lines
• Who was studied: Male SCID mice (6 weeks old), two diet groups of five animals each; four human malignant mesothelioma cell lines derived from pleural effusion (NCI-H2052, NCI-H28, NCI-H2452, MSTO-211H), with a human A673 rhabdomyosarcoma cell line as a positive control; Tohoku University, Sendai, Japan
• Exposure: No asbestos exposure was studied. Mice received a 20% corn oil diet or a 20% menhaden fish oil diet (10–15% EPA and 8–15% DHA). Cell lines were treated with adiponectin, COX-2 inhibitors (Meloxicam, NS-398), an AMPK activator (AICAR) and an AMPK inhibitor (compound C).
• Main results:
  • There were no significant differences in food intake or weight gain between the corn oil and fish oil mouse groups
  • Tumor growth rate and tumor weight (after 25 days) were significantly lower in the fish oil diet group than in the corn oil diet group
  • The fish oil diet increased serum adiponectin concentration in the mice
  • In the mice, serum adiponectin concentration was strongly related to tumor weight (R-squared 0.76, P = 0.001)
  • Tumor adiponectin and phospho-AMPK protein levels were 180% and 160% greater in the fish oil group than in the corn oil group
  • Tumor COX-2 protein level was 30% lower in the fish oil group than in the corn oil group
  • In tumors from the fish oil group, the rate of Ki67-positive (proliferating) cells was significantly lower, and the rate of TUNEL-positive (apoptotic) cells was greater, than in the corn oil group
  • In all four mesothelioma cell lines, 24-hour adiponectin treatment significantly impaired cell proliferation in a dose-dependent manner
  • In NCI-H2452 and MSTO-211H cells, adiponectin increased annexin V-positive (apoptotic) cells and decreased DNA synthesis; activated caspase-3 was detected in adiponectin-treated cells but not in control cells
  • All four mesothelioma cell lines expressed adiponectin receptors AdipoR1 and AdipoR2 at the mRNA and protein levels
  • In NCI-H2452 and MSTO-211H cells, adiponectin significantly decreased COX-2 protein and prostaglandin E2 levels
  • The AMPK inhibitor compound C prevented the effect of adiponectin on phospho-AMPK and COX-2 levels
  • Silencing AdipoR1 with siRNA strongly abolished the adiponectin-induced decrease in COX-2 and increase in phospho-AMPK; silencing AdipoR2 did not
  • In NCI-H2452 and MSTO-211H cells treated with control siRNA, adiponectin impaired cell proliferation by 15%. This effect was significantly restored by AdipoR1 siRNA but not by AdipoR2 siRNA
• The authors' conclusion: The authors concluded that inducing or supplementing adiponectin is an important tactic for therapeutic strategies for malignant mesothelioma. They also suggested the results may bear on preventive strategies for people previously exposed to asbestos.
• Limitations the authors state:
  • The authors stated that the mechanism by which AMPK might interact with COX-2 is unclear and requires further study

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Latency, Asbestos Exposure, Prognosis, Fluorescence In Situ Hybridization (FISH), Apoptosis.

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