Epithelial cells are the basic cell
type that lines various body cavities and organs throughout the body,
forming a protective barrier against toxins, pathogens and inflammatory
Researchers at University of California San Diego School of Medicine
have identified a previously unknown mechanism that helps fortify the
structure and tight junctions between epithelial cells. Breaches of this barrier can provoke organ dysfunction and
development of tumors.
‘New insights into the epithelium-protecting and tumor-suppressive actions of one of the most widely prescribed diabetes drugs, Metformin, has been provided by researchers.’
The findings, published online in the current issue of eLife
by senior author Pradipta Ghosh, professor in the departments of
Medicine and Cellular and Molecular Medicine at UC San Diego School of
Medicine, and colleagues, helps illuminate why the widely prescribed
anti-diabetic drug Metformin has repeatedly been shown to not only
protect epithelial integrity in the face of stressors like inflammation,
sepsis, hypoxia and harmful microbes, but also appears to prevent
Virtually all cell types possess cell polarity - the asymmetrical
organization of their components and structures that makes it possible
for them to carry out specialized functions. In epithelial cells,
polarity determines how they form barriers. Loss of epithelial polarity
impacts organ development and function and can initiate cancers.
The stress-polarity pathway, discovered and described in 2006 and
2007, is a specialized pathway mobilized only during periods of stress.
It is orchestrated by a protein-kinase called AMPK that protects
cellular polarity when epithelial cells are under energetic stress and
an activator of AMPK called LBK1.
"The latter is a bona fide tumor suppressor," said Ghosh. Mutations
in LBK1 have been linked to cancers and loss of cell polarity. While the
question of exactly how the energy-sensing LKB1-AMPK pathway maintains
cell polarity during stress remained unknown for more than a decade,
evidence accumulated that Metformin, an activator of the LKB1-AMPK
pathway and a frontline treatment for type 2 diabetes, has beneficial
effects on the epithelial lining and can potentially prevent cancer.
The new research, said Ghosh, provides "mechanistic insights into
the tumor suppressive action of Metformin and the LKB1-AMPK pathway at a
higher resolution." Specifically, she and colleagues discovered that
the stress-polarity pathway requires a key effector of AMPK - a protein
In cultured polarized epithelial cells, the authors demonstrated
that AMPK and its activator Metformin exerted much of their beneficial
effects via phosphorylating GIV and directing GIV to the tight junctions
of the epithelial layer. Without such phosphorylation and/or targeting,
the beneficial effects of AMPK, and its activator Metformin, were
virtually abolished and the epithelial barrier became "leaky" and
eventually collapsed. Mutants of GIV found in colon cancer that
specifically abolish AMPK's ability to phosphorylate GIV could trigger
tumor cell growth in 3D matrigel.
"In summary, by identifying GIV/Girdin as a key layer within the
stress-polarity pathway we've peeled another layer of the proverbial
onion," Ghosh said. "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."