Abstract
Cancer cells utilise the glycolytic pathway to support their rapid growth and proliferation. Since cells in most solid tumours are subjected to severe microenvironmental stresses including low nutrient and oxygen availability, such cancer cells must develop mechanisms to overcome these unfavourable growth conditions by metabolic adaptation. Although the liver kinase B1 (LKB1)-adenosine monophosphate-activated kinase (AMPK) signalling pathway plays a pivotal role in maintaining energy homeostasis under conditions of metabolic stress, the role of LKB1-AMPK signalling in aiding cancer cell survival and in malignant tumours has not yet been fully elucidated. We show that glucose starvation promotes cancer cell invasiveness and migration through LKB1-AMPK-regulated MMP-9 expression. Most intriguingly, triggering the LKB1-AMPK signalling pathway by glucose starvation-induced oxidative stress facilitates selective autophagy, which in turn enhances Keap1 degradation and the subsequent activation of Nrf2. Following this, Nrf2 regulates the transactivation of MMP-9 via Nrf2 binding sites in the promoter region of the MMP-9 gene. These mechanisms also contribute to the suppression of excessive oxidative stress under glucose starvation, and protect against cell death. Our data clearly shows that LKB1-AMPK signalling not only maintains energy and oxidative stress homeostasis, but could also promote cancer progression during metabolic stress conditions by MMP-9 induction.
Highlights
Cancer cells exhibit significant alterations in metabolic pathways that support cell mass accumulation, nucleic acid biosynthesis, and mitotic cell division[1,2]
In order to investigate if Matrix metalloproteinases (MMPs)-9 is involved in enhancing the migration and invasive capacity of cancer cells induced by glucose starvation, we examined the expression of matrix metalloproteinase-9 (MMP-9) in glucose-starved cells, and tried to determine if this expression of MMP-9 was dependent on the activation of the liver kinase B1 (LKB1)-AMPK signalling pathway in several human cancer cell lines
Our observations strongly suggest that LKB1-AMPK activation is involved in autophagy during glucose starvation, and regulates autophagy-mediated maintenance of redox balance in cells, all of which integrate into the mechanism that leads to the induction of MMP-9 expression to help cells escape from severe metabolic stress
Summary
Cancer cells exhibit significant alterations in metabolic pathways that support cell mass accumulation, nucleic acid biosynthesis, and mitotic cell division[1,2]. The liver kinase B1 (LKB1)-adenosine monophosphate-activated kinase (AMPK) signalling pathway is a key energy sensor in normal and cancer cells that plays a central role in sensing energy availability in the cell; it induces metabolic adaptation pathways to ensure cell survival. The LKB1-AMPK pathway promotes cell survival during glucose starvation by either inhibiting the mammalian target of rapamycin (mTOR) or by activating the tumour suppressor p5322,23. AMPK promotes cancer cell survival by regulating intracellular NADPH homeostasis during metabolic stress caused by glucose starvation[24]. Accumulating evidence further suggests that AMPK activation could be important for the development of malignant tumour characteristics in several types of cancer[12,13,14,15] It remains to be determined if the protective effects of the LKB1-AMPK signalling pathway under oxidative stress and glucose starvation conditions can affect cancer cell migration and invasiveness
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
