Transforming growth factor-β-induced protein (TGFBI) suppresses mesothelioma progression through the Akt/mTOR pathway

Our plain-English summary of Transforming growth factor-β-induced protein (TGFBI) suppresses mesothelioma progression through the Akt/mTOR pathway, by G. Wen, M. Hong, B. Li, et al (International Journal of Oncology, 2011).

The study

• Authors: G. Wen, M. Hong, B. Li, W. Liao, S.K. Cheng, B. Hu, G.M. Calaf, P. Lu, M.A. Partridge, J. Tong, T.K. Hei
• Journal: International Journal of Oncology
• Published: 2011;39(4):1001-9
• Cited by: 34 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

As an uncommon cancer, mesothelioma is very hard to treat with a low average survival rate owing to its usual late detection and being highly invasive. The link between asbestos exposure and the development of mesothelioma in humans is unequivocal. TGFBI, a secreted protein that is induced by transforming growth factor-β in various human cell types, has been shown to be associated with tumorigenesis in various types of tumors. It has been demonstrated that TGFBI expression is markedly suppressed in asbestos-induced tumorigenic cells, while an ectopic expression of TGFBI significantly suppresses tumorigenicity and progression in human bronchial epithelial cells. In order to delineate a potential role of TGFBI in mediating the molecular events that occur in mesothelioma tumorigenesis, we generated stable TGFBI knockdown mutants from the mesothelium cell line Met-5A by using an shRNA approach, and secondly created ectopic TGFBI overexpression mutants from the mesothelioma cell line H28 in which TGFBI is absent. We observed that in the absence of TGFBI, the knockdown mesothelial and mesothelioma cell lines exhibited an elevated proliferation rate, enhanced plating efficiency, increased anchorage-independent growth, as well as an increased cellular protein synthesis rate as compared with their respective controls. Furthermore, cell cycle regulatory proteins c-myc/cyclin D1/phosphor-Rb were upregulated; a more active PI3K/Akt/mTOR signaling pathway was also detected in TGFBI-depleted cell lines. These findings suggest that TGFBI may repress mesothelioma tumorigenesis and progression via the PI3K/Akt signaling pathway.

In plain English

This was a laboratory study of two human cell lines grown in dishes. No people were studied, and the cells were not exposed to asbestos in this study. The authors examined a protein called TGFBI, which their group had earlier reported to be reduced in asbestos-transformed bronchial cells. They lowered TGFBI in a non-cancerous mesothelial cell line (Met-5A) and added TGFBI to a mesothelioma cell line (H28) that lacks it. Cells lacking TGFBI grew faster, formed more colonies from single cells and made protein faster than comparison cells with TGFBI. Met-5A cells with lowered TGFBI also grew more in soft agar, a laboratory sign of cancer-like behavior. Three cell-cycle proteins showed 2- to 4-fold increases in cells lacking TGFBI. Signals in the Akt/mTOR growth pathway were stronger in these cells, both with and without growth-factor stimulation. The authors concluded that TGFBI suppresses mesothelioma progression through the Akt/mTOR pathway and may be a target for future treatments. They noted that one proposed mechanism remains to be tested, and that other studies found TGFBI increased spread of colon and ovarian cancer cells.

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-culture experiment
• Who was studied: Two human cell lines: the non-malignant mesothelial cell line Met-5A and the mesothelioma cell line H28, which does not make TGFBI. No human subjects.
• Exposure: No asbestos exposure in this study. The cells were genetically altered: TGFBI was knocked down in Met-5A cells and added to H28 cells. Some experiments stimulated cells with epidermal growth factor (EGF).
• Main results:
  • Met-5A cells with TGFBI knocked down (5AT1, 5AT2) grew faster than control Met-5A cells (5ATE, 5ATN) after day 4.
  • H28 mesothelioma cells without TGFBI (H28, H28V) grew faster than H28 cells given TGFBI (H28T6, H28T7).
  • Plating efficiency (colony formation from single cells) followed the same pattern as growth rate.
  • The cell-cycle proteins c-myc, cyclin D1 and phosphorylated Rb were increased 2- to 4-fold in TGFBI-lacking cells (5AT1 and H28V) compared with TGFBI-expressing controls (5ATE and H28T7).
  • Anchorage-independent growth (growth in soft agar) was significantly increased in TGFBI-knockdown Met-5A cells (5AT1, 5AT2) compared with controls (5ATN, 5ATE).
  • After EGF stimulation, Akt activation (phosphorylation) was stronger in TGFBI-knockdown 5AT1 cells than in control 5ATE cells.
  • Without external stimulation, activation of Akt, mTOR, S6K and 4EBP1 was higher in TGFBI-deficient cell lines (5AT1, H28V) than in TGFBI-expressing lines (5ATE, H28T7).
  • Protein synthesis rate was significantly higher in cells without TGFBI (5AT1 and H28V) than in their TGFBI-expressing counterparts.
  • In TGFBI-knockdown 5AT1 cells, binding of the PI3K subunit p85 to the EGF receptor was increased compared with 5ATE cells, peaking at 10 minutes.
• The authors' conclusion: The authors concluded that TGFBI suppresses mesothelioma progression through the Akt/mTOR pathway, and suggested that TGFBI may be a target for designing future anti-mesothelioma treatments.
• Limitations the authors state:
  • The authors' proposed explanation, that TGFBI may act by binding the growth factor receptor, has not been tested.
  • Other studies found that TGFBI increased the metastatic ability of colon and ovarian cancer cell lines. The authors said it needs to be determined whether TGFBI's effect depends on cell type.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Asbestos Exposure, Tumorigenesis, Mesothelium.

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• Multipoint targeting of the PI3K/mTOR pathway in mesothelioma — S. Zhou, L. Liu, et al. (2014)
• Combined Inhibition of NEDD8-Activating Enzyme and mTOR Suppresses NF2 Loss-Driven Tumorigenesis — J. Cooper, Q. Xu, et al. (2017)
• PARP1 inhibition affects pleural mesothelioma cell viability and uncouples AKT/mTOR axis via SIRT1 — G. Pinton, A.G. Manente, et al. (2013)
• Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells — M. Bonelli, R. Terenziani, et al. (2020)
• Distribution of transforming growth factor-beta 1, fibronectin, and smooth muscle actin in asbestos-induced pulmonary fibrosis in rats — T.D. Perdue, A.R. Brody (1994)

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