Researchers have uncovered a previously unknown molecular mechanism that works at the cell level to help protect the epithelial tissue that lines various body cavities and organs in the body. The discovery may help explain why the widely prescribed diabetes drug metformin appears to preserve the epithelial barrier’s ability to ward off infection, resist inflammation, and suppress tumors.
The team – from the University of California-San Diego School of Medicine – reports the findings in the journal eLife.
The study concerns cells of the epithelium, one of the four main tissue types of the human body – the others are connective, muscle, and nerve tissue. The epithelium lines various cavities and organs and covers flat surfaces.
There is a feature common to nearly all cells called polarity – the asymmetric organization of internal components and shape.
Without this “knowing which way is up” feature, epithelial cells cannot carry out specialized functions, such as maintaining a protective barrier against toxins, disease-causing agents, and triggers of inflammation.
Loss of epithelial cell polarity can cause a breach in the barrier that leads to organ dysfunction and development of tumors.
The new study identifies a previously unknown mechanism that helps strengthen the structure and tight junctions between epithelial cells so they can maintain the barrier.
Metformin activates LKB1-AMPK stress-polarity pathway
Previous studies have shown that the widely prescribed diabetes drug metformin helps preserve the epithelial barrier’s ability to resist stressors such as inflammation, sepsis, low oxygen (hypoxia), and harmful microbes. It also appears to help the barrier suppress tumors.
Other studies published some 10 years ago also uncovered a “stress-polarity” pathway that is only activated when the epithelial cells come under stress.
The pathway is switched on when an enzyme called AMPK – that protects cellular polarity under conditions of stress – is triggered by a tumor suppressor molecule called LKB1.
Senior author Pradipta Ghosh, professor in the departments of Medicine and Cellular and Molecular Medicine, describes LKB1 as a “bona fide tumor suppressor,” mutations in which have been linked to cancers and loss of cell polarity.
For the past 10 years, the question of how the energy-sensing LKB1-AMPK pathway maintains cell polarity during stress has remained unanswered.
However, in the meantime, it has come to light that metformin – a front-line treatment for type 2 diabetes – is an activator of the LKB1-AMPK pathway.
Metformin acts via GIV phosphorylation
In their new study, Prof. Ghosh and colleagues investigated the mechanisms involved in the tumor-suppressive effect of metformin on the LKB1-AMPK pathway.
They discovered that the pathway depends on a key effector – a triggering molecule – of AMPK, a protein called GIV/Girdin.
GIV/Girdin is itself activated by a process called “phosphorylating” (the chemical addition of a phosphate group).
Using cultured polarized epithelial cells, the team showed much of the beneficial effect of metformin on AMPK occurred via phosphorylating GIV and directing it to the tight junctions of the epithelial layer.
In another set of experiments, the researchers found the beneficial effects of metformin activating AMPK virtually disappeared in the absence of GIV phosphorylation. This also resulted in a “leaky” epithelial barrier that eventually collapsed.
Finally, the researchers showed that mutant forms of GIV found in colon cancer that prevent its phosphorylation by AMPK led to tumor cell growth.
“In summary, by identifying GIV/Girdin as a key layer within the stress-polarity pathway we’ve peeled another layer of the proverbial onion. In the process, we’ve provided new insights into the epithelium-protecting and tumor-suppressive actions of one of the most widely prescribed drugs, metformin, which may inspire a fresh look and better designed studies to fully evaluate the benefits of this relatively cheap medication.”
Prof. Pradipta Ghosh