A selective phosphatase of regenerating liver phosphatase inhibitor suppresses tumor cell anchorage-independent growth by a novel mechanism involving p130Cas cleavage

Sherif Daouti, Wen Hui Li, Hong Qian, Kuo Sen Huang, Janna Holmgren, Wayne Levin, Linda Reik, Debra Lucas McGady, Paul Gillespie, Agostino Perrotta, Hongjin Bian, John F. Reidhaar-Olson, Sarah A. Bliss, Andree R. Olivier, Joseph A. Sergi, David Fry, Waleed Danho, Steve Ritland, Nader Fotouhi, David Heimbrook & 1 others Huifeng Niu

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

The phosphatase of regenerating liver (PRL) family, a unique class of oncogenic phosphatases, consists of three members: PRL-1, PRL-2, and PRL-3. Aberrant overexpression of PRL-3 has been found in multiple solid tumor types. Ectopic expression of PRLs in cells induces transformation, increases mobility and invasiveness, and forms experimental metastases in mice. We have now shown that small interfering RNA-mediated depletion of PRL expression in cancer cells results in the down-regulation of p130Cas phosphorylation and expression and prevents tumor cell anchorage-independent growth in soft agar. We have also identified a small molecule, 7-amino-2-phenyl-5H-thieno[3,2-c]pyridin-4-one (thienopyridone), which potently and selectively inhibits all three PRLs but not other phosphatases in vitro. The thienopyridone showed significant inhibition of tumor cell anchorage-independent growth in soft agar, induction of the p130Cas cleavage, and anoikis, a type of apoptosis that can be induced by anticancer agents via disruption of cell-matrix interaction. Unlike etoposide, thienopyridone-induced p130Cas cleavage and apoptosis were not associated with increased levels of p53 and phospho-p53 (Ser15), a hallmark of genotoxic drug-induced p53 pathway activation. This is the first report of a potent selective PRL inhibitor that suppresses tumor cell three-dimensional growth by a novel mechanism involving p130Cas cleavage. This study reveals a new insight into the role of PRL-3 in priming tumor progression and shows that PRL may represent an attractive target for therapeutic intervention in cancer.

Original languageEnglish (US)
Pages (from-to)1162-1169
Number of pages8
JournalCancer Research
Volume68
Issue number4
DOIs
StatePublished - Feb 15 2008
Externally publishedYes

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Phosphoric Monoester Hydrolases
Liver
Growth
Neoplasms
Agar
Anoikis
Apoptosis
Etoposide
Cell Communication
Antineoplastic Agents
Small Interfering RNA
Down-Regulation
Phosphorylation
Neoplasm Metastasis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

A selective phosphatase of regenerating liver phosphatase inhibitor suppresses tumor cell anchorage-independent growth by a novel mechanism involving p130Cas cleavage. / Daouti, Sherif; Li, Wen Hui; Qian, Hong; Huang, Kuo Sen; Holmgren, Janna; Levin, Wayne; Reik, Linda; McGady, Debra Lucas; Gillespie, Paul; Perrotta, Agostino; Bian, Hongjin; Reidhaar-Olson, John F.; Bliss, Sarah A.; Olivier, Andree R.; Sergi, Joseph A.; Fry, David; Danho, Waleed; Ritland, Steve; Fotouhi, Nader; Heimbrook, David; Niu, Huifeng.

In: Cancer Research, Vol. 68, No. 4, 15.02.2008, p. 1162-1169.

Research output: Contribution to journalArticle

Daouti, S, Li, WH, Qian, H, Huang, KS, Holmgren, J, Levin, W, Reik, L, McGady, DL, Gillespie, P, Perrotta, A, Bian, H, Reidhaar-Olson, JF, Bliss, SA, Olivier, AR, Sergi, JA, Fry, D, Danho, W, Ritland, S, Fotouhi, N, Heimbrook, D & Niu, H 2008, 'A selective phosphatase of regenerating liver phosphatase inhibitor suppresses tumor cell anchorage-independent growth by a novel mechanism involving p130Cas cleavage', Cancer Research, vol. 68, no. 4, pp. 1162-1169. https://doi.org/10.1158/0008-5472.CAN-07-2349
Daouti, Sherif ; Li, Wen Hui ; Qian, Hong ; Huang, Kuo Sen ; Holmgren, Janna ; Levin, Wayne ; Reik, Linda ; McGady, Debra Lucas ; Gillespie, Paul ; Perrotta, Agostino ; Bian, Hongjin ; Reidhaar-Olson, John F. ; Bliss, Sarah A. ; Olivier, Andree R. ; Sergi, Joseph A. ; Fry, David ; Danho, Waleed ; Ritland, Steve ; Fotouhi, Nader ; Heimbrook, David ; Niu, Huifeng. / A selective phosphatase of regenerating liver phosphatase inhibitor suppresses tumor cell anchorage-independent growth by a novel mechanism involving p130Cas cleavage. In: Cancer Research. 2008 ; Vol. 68, No. 4. pp. 1162-1169.
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AU - Holmgren, Janna

AU - Levin, Wayne

AU - Reik, Linda

AU - McGady, Debra Lucas

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AU - Bian, Hongjin

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AU - Bliss, Sarah A.

AU - Olivier, Andree R.

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AU - Fry, David

AU - Danho, Waleed

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