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Involvement of E-cadherin/AMPK/mTOR axis in LKB1-induced sensitivity of non-small cell lung cancer to gambogic acid.

08:00 EDT 9th September 2019 | BioPortfolio

Summary of "Involvement of E-cadherin/AMPK/mTOR axis in LKB1-induced sensitivity of non-small cell lung cancer to gambogic acid."

Liver kinase B1 (LKB1) is a tumor suppressor that functions as master regulator of cell growth, metabolism, survival, and polarity. Patientswith NSCLC possessing mutated LKB1 respond to chemotherapy differently from those with wild-type LKB1. Gambogic acid (GA), a small molecule from natural product, has been established as an anti-tumor agent due to its potent activity and low toxicity. Here, we find out that NSCLC cells with wild-type LKB1 are more sensitive to GA in vitro and in vivo. Mechanistic studies pinpoint that the selective inhibition of mTOR signaling confers the stronger suppression of NSCLC in presence of wild-type LKB1, which is involved in the enhancement of p-AMPK. Further studies reveal that GA increases p-AMPK levels through up-regulation of E-cadherin associated with LKB1. In addition, induction of E-cadherin by GA may be through down-regulation of ZEB1, which is independent with LKB1 status. Hence, our findings support that enhanced E-cadherin by GA cooperates LKB1, leading to up-regulation of p-AMPK , and thus blocking of mTOR signaling pathway, which provide theoretical foundation for utilization of GA as a potential targeted drug against NSCLC harboring wild-type LKB1.

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This article was published in the following journal.

Name: Biochemical pharmacology
ISSN: 1873-2968
Pages: 113635

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Medical and Biotech [MESH] Definitions

An adaptor protein, consisting of seven WD REPEATS along its length, that functions as a component of the MECHANISTIC TARGET OF RAPAMYCIN COMPLEX 1 and MTORC2 COMPLEX. It interacts directly with MTOR to enhance its kinase activity and stabilizes the MTOR-RPTOR PROTEIN interaction in nutrient-poor conditions, favoring RPTOR inhibition of MTOR activity.

Membrane proteins that contain at least two typical consecutive CADHERIN motifs but typically more than cadherin or protocadherin proteins. Their overall domain organization also differs from those of cadherins and protocadherins, and contains different and unique cytoplasmic domains.

Calcium-dependent cell adhesion proteins. They are important in the formation of ADHERENS JUNCTIONS between cells. Cadherins are classified by their distinct immunological and tissue specificities, either by letters (E- for epithelial, N- for neural, and P- for placental cadherins) or by numbers (cadherin-12 or N-cadherin 2 for brain-cadherin). Cadherins promote cell adhesion via a homophilic mechanism as in the construction of tissues and of the whole animal body.

The rotational force about an axis that is equal to the product of a force times the distance from the axis where the force is applied.

A multiprotein complex consisting of MTOR KINASE; MLST8 PROTEIN; rapamycin-insensitive companion of mTOR protein (RICTOR PROTEIN); and PRR5 (proline-rich protein 5). Like MTORC1, it also regulates cell growth and proliferation in response to growth factors but may not be as sensitive to nutrient availability and is insensitive to SIROLIMUS. In contrast to MTORC1, it can regulate the ACTIN CYTOSKELETON through RHO GTPASES to promote the formation of STRESS FIBERS. The mTORC2 complex also plays a critical role in AKT1 PROTEIN KINASE phosphorylation and activation.

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