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 Purdue University’s Zhong-Yin Zhang’s team has
discovered a novel “phosphatase cascade” that plays a critical role
in pancreas, liver, kidney, lung, breast, prostate, brain and
other types of cancers. Their findings, published today in the
Proceedings of the National Academy of Sciences, show that a
“pro-oncogenic” phosphatase PRL2 exerts its effect by
down-regulating PTEN, a tumor-suppressive phosphatase frequently
lost in human cancers.
“This suggests that PRL2 could be a cancer drug target,” said Zhang,
Distinguished Professor of Medicinal Chemistry, the Robert C. and
Charlotte P. Anderson Chair in Pharmacology and director of the
Purdue Institute for Drug Discovery. “Rather than targeting kinases
in the PI3K-AKT pathway, which has seen limited efficacy due to both
on- and off-target side effects, we may be able to inhibit the PRL2
phosphatase and restore levels of PTEN to suppress tumor formation.
That’s exciting and could impact many forms of cancer.”
Kinases attach phosphate groups to proteins while phosphatases
remove them, and both have the potential to change proteins in ways
that turn cells cancerous. Zhang’s team showed that PRL2 removes a
phosphate from tyrosine 336 in PTEN. When that happens, PTEN is
ubiquitinated, or essentially marked for degradation, lowering its
levels and ability to fight cancer progression.
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The scientists discovered that high PRL2 expression
is correlated with low PTEN level and reduced overall patient
survival in several human malignancies. When PRL2 was deleted from a
cancer-prone, PTEN-deficient mouse model, PTEN levels returned to
normal and cancer progression ceased.
“This sheds light on how PRL2 causes cancer and
validates it as a target for PTEN-restoration therapy,” said Zhang,
who is a member of the Purdue Center for Cancer Research. “It also
shows the potential for looking not only to kinases as a way to
inhibit tumorigenesis, but also to phosphatases.”
Zhang’s lab earlier identified a promising method for PRL2
inhibition. PRL2 functions as a trimer, and the molecule Cmdp-43 has
been shown to disrupt the ability of PRL2 to come together. Zhang is
continuing development of the drug.
The National Institutes of Health and the Robert C. and Charlotte
Anderson Chair Endowment provided funding for Zhang’s research.
[Writer: Brian Wallheimer
Source: Zhong-Yin Zhang]
The ACS is currently funding the
following research at Purdue University:
Targeting Matrix-Mediated Drug
Resistance in Metastatic Breast Cancer - $792,000
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