Mediterranean diet takes away cancer cells’ “superpower” to escape death.
By altering a very specific step in gene regulation, this compound
essentially re-educates cancer cells into normal cells that die as
One way that cancer cells thrive is by inhibiting a process that would cause
them to die on a regular cycle that is subject to strict programming. This
study in cells, led by Ohio State University researchers, found that a
compound in certain plant-based foods, called apigenin, could stop breast
cancer cells from inhibiting their own death.
Much of what is known about the health benefits of nutrients is based on
epidemiological studies that show strong positive relationships between
eating specific foods and better health outcomes, especially reduced heart
disease. But how the actual molecules within these healthful foods work in
the body is still a mystery in many cases, and particularly with foods
linked to lower risk for cancer.
Parsley, celery and chamomile tea are the most common sources of apigenin,
but it is found in many fruits and vegetables.
The researchers also showed in this work that apigenin binds with an
estimated 160 proteins in the human body, suggesting that other nutrients
linked to health benefits – called “nutraceuticals” – might have similar
far-reaching effects. In contrast, most pharmaceutical drugs target a single
“We know we need to eat healthfully, but in most cases we don’t know the
actual mechanistic reasons for why we need to do that,” said Andrea Doseff,
associate professor of internal medicine and molecular genetics at Ohio
State and a co-lead author of the study. “We see here that the beneficial
effect on health is attributed to this dietary nutrient affecting many
proteins. In its relationship with a set of specific proteins, apigenin
re-establishes the normal profile in cancer cells. We think this can have
great value clinically as a potential cancer-prevention strategy.”
Doseff oversaw this work with co-lead author Erich Grotewold, professor of
molecular genetics and director of Ohio State’s Center for Applied Plant
Sciences (CAPS). The two collaborate on studying the genomics of apigenin
and other flavonoids, a family of plant compounds that are believed to
The research appears this week in the online early edition of the journal
Proceedings of the National Academy of Sciences.
Though finding that apigenin can influence cancer cell behavior was an
important outcome of the work, Grotewold and Doseff point to their new
biomedical research technique as a transformative contribution to
They likened the technique to “fishing” for the human proteins in cells that
interact with small molecules available in the diet.
“You can imagine all the potentially affected proteins as tiny fishes in a
big bowl. We introduce this molecule to the bowl and effectively lure only
the truly affected proteins based on structural characteristics that form an
attraction,” Doseff said. “We know this is a real partnership because we can
see that the proteins and apigenin bind to each other.”
Through additional experimentation, the team established that apigenin had
relationships with proteins that have three specific functions. Among the
most important was a protein called hnRNPA2.
This protein influences the activity of messenger RNA, or mRNA, which
contains the instructions needed to produce a specific protein. The
production of mRNA results from the splicing, or modification, of RNA that
occurs as part of gene activation. The nature of the splice ultimately
influences which protein instructions the mRNA contains.
Doseff noted that abnormal splicing is the culprit in an estimated 80
percent of all cancers. In cancer cells, two types of splicing occur when
only one would take place in a normal cell – a trick on the cancer cells’
part to keep them alive and reproducing.
In this study, the researchers observed that apigenin’s connection to the
hnRNPA2 protein restored this single-splice characteristic to breast cancer
cells, suggesting that when splicing is normal, cells die in a programmed
way, or become more sensitive to chemotherapeutic drugs.
“So by applying this nutrient, we can activate that killing machinery. The
nutrient eliminated the splicing form that inhibited cell death,” said
Doseff, also an investigator in Ohio State’s Davis Heart and Lung Research
Institute. “Thus, this suggests that when we eat healthfully, we are
actually promoting more normal splice forms inside the cells in our bodies.”
The beneficial effects of nutraceuticals are not limited to cancer, as the
investigators previously showed that apigenin has anti-inflammatory
The scientists noted that with its multiple cellular targets, apigenin
potentially offers a variety of additional benefits that may even occur over
time. “The nutrient is targeting many players, and by doing that, you get
an overall synergy of the effect,” Grotewold explained.
Doseff is leading a study in mice, testing whether food modified to contain
proper doses of this nutrient can change splicing forms in the animals’
cells and produce an anti-cancer effect.
Additional co-authors are first author Daniel Arango, a Ph.D. student in the
Molecular, Cellular and Developmental Biology graduate program; and Kengo
Morohashi, Alper Yilmaz, Arti Parihar and undergraduate Bledi Brahimaj of
the Department of Molecular Genetics, all at Ohio State; and Kouji Kuramochi
of Kyoto Prefectural University in Japan. Doseff, Arango and Parihar are
affiliated with Ohio State’s Division of Pulmonary, Allergy, Critical Care
and Sleep Medicine.
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