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How the Suppression of AMPK by Growth Factor Midkine Promotes Cancer Progression

Scientists have discovered a novel function of the growth factor Midkine and how it contributes to cancer cell proliferation by mediating AMPK signalling.

Led by Professor Piao Hailong from the Dalian Institute of Chemical Physics (DICP) of the Chinese Academy of Sciences (CAS), a group of researchers have discovered a novel function of growth factor Midkine to suppress the Liver Kinase B1 / AMP-Activated Protein Kinase (LKB1-AMPK) axis in a noncanonical intracellular fashion. They found that by interfering with the LKB1-STRAD-Mo25 (STRAD: STE20-Related Kinase Adaptor) complex, Midkine can reduce LKB1 activity and attenuate AMPK phosphorylation to encourage cancer cell proliferation and tumour progression.

Belonging to the pleiotrophin family growth factor, Midkine participates in various physiological processes such as inflammatory processes. In particular, Midkine promotes tumour growth and invasion by enhancing tumour angiogenesis. Upon signal peptide cleavage, Midkine is secreted to the extracellular space like that of other growth factors. The secreted then Midkine acts as a ligand and binds to different transmembrane receptors to induce intracellular signalling. In several studies, scientists have reported that the secreted Midkine can be transported back into cells via endocytosis. However, it remains unclear whether intracellular Midkine performs biological functions.

In the current study, Piao and colleagues not only discovered that the relocalisation of Midkine is very efficient, but also that the internalised Midkine is mainly found in the cytoplasm, suggesting a previously unknown intracellular function of Midkine. Upon focusing on AMPK signalling, it was found that Midkine can suppress AMPK phosphorylation at the Thr172 site of the α subunit, resulting in the inactivation of AMPK in an intracellular dependent manner. When Midkine was detained in extracellular space by heparin, the repression of Midkine to AMPK was relieved.

In addition, the researchers discovered that Midkine suppresses AMPK activation through the upstream kinase LKB1. Through mass spectrometry analysis and immunoprecipitation test, it was proven that Midkine associates with LKB1 and STRAD to disrupt the LKB1-STRAD-Mo25 complex, which is required to activate LKB1. By engineering the expression of Midkine and LKB1, the researchers established that Midkine promotes cancer cell proliferation through the LKB1-AMPK axis. Clinical data analysis further verified that the expression of Midkine was negatively related to AMPK activity and patient prognosis.

The results of this study would provide more clues towards the clinical use of MDK in cancer diagnosis and prognosis. [APBN]

Source: Xia et al. (2022). Midkine noncanonically suppresses AMPK activation through disrupting the LKB1-STRAD-Mo25 complex.Cell death & disease,13(4), 1-13.