Princeton Docket #
The ability to
selectively kill quiescent cells could be a powerful tool in medicine. In
particular, the ability to kill the quiescent tumor stem cells could be an
important addition to our chemotherapeutic repertoire. A better understanding of
the transition between quiescent and activated cellular states of fibroblasts
may also suggest new strategies to treat fibrotic disease.
technology, researchers in the department of Molecular Biology at Princeton
University have discovered that the pentose phosphate pathway is active in
cultured primary dermal fibroblasts made quiescent by contact inhibition.
Treatment with a small molecule inhibitor of the pentose phosphate pathway for 4
days resulted in a higher induction of apoptosis in quiescent, contact-inhibited
fibroblasts than in proliferating fibroblasts. Induction of apoptosis was even
higher in fibroblasts made quiescent by a second method, serum starvation.
dermal fibroblasts are also found to activate autophagy. Treating proliferating
and quiescent fibroblasts with an inhibitor of autophagy resulted in a
time-dependent induction of apoptosis in serum-starved fibroblasts but had
little effect on proliferating or contact-inhibited fibroblasts.
treatment with both the pentose phosphate pathway inhibitor and the autophagy
inhibitor was found to be more effective in inducing apoptosis in quiescent,
serum-starved cells than treatment with either inhibitor alone. Pentose
phosphate pathway inhibition alone resulted in a six-fold induction of apoptosis
after 24 hours, while autophagy inhibition alone had less than a two-fold effect
on apoptosis. Pentose phosphate pathway inhibition in combination with autophagy
inhibition resulted in an approximately sixteen-fold induction of apoptosis in
the serum-starved fibroblasts after 24 hours. In contact-inhibited fibroblasts,
the induction was approximately four-fold in response to both inhibitors. In
proliferating fibroblasts, the induction was approximately two-fold.
Hilary Coller is an
assistant professor of molecular biology at Princeton University. The Coller lab
uses genomic approaches to gain insight into cell cycle control in normal
tissues and cancer. Because uncontrolled cell division is so dangerous for an
organism, the well-behaved cell must know not only when to divide,
but¿crucially¿when not to. Shutting down cell division prevents tumors and
maintains the proper form of tissues. Many cells, though, including fibroblasts,
must also retain the ability to start dividing again when conditions are
right¿when the organism must grow, or a damaged tissue must be repaired. A cell
in such a temporary, non-dividing state is said to be ¿quiescent.¿ Signals that
send a cell into quiescence include loss of contact with the underlying surface,
too much contact with neighboring cells, and not receiving specific growth
factors from the surroundings.
Lemons JM, Feng XJ,
Bennett BD, Legesse-Miller A, Johnson EL, Raitman I, Pollina EA, Rabitz HA,
Rabinowitz JD, Coller HA. (2010) Quiescent fibroblasts exhibit high metabolic
activity. PLoS Biol. 8: e1000514. (Selected for Nature Research Highlights
and Faculty of 1000).
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