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Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer.

Publication ,  Journal Article
Proffitt, KD; Madan, B; Ke, Z; Pendharkar, V; Ding, L; Lee, MA; Hannoush, RN; Virshup, DM
Published in: Cancer Res
January 15, 2013

Porcupine (PORCN) is a membrane bound O-acyltransferase that is required for Wnt palmitoylation, secretion, and biologic activity. All evaluable human Wnts require PORCN for their activity, suggesting that inhibition of PORCN could be an effective treatment for cancers dependent on excess Wnt activity. In this study, we evaluated the PORCN inhibitor Wnt-C59 (C59), to determine its activity and toxicity in cultured cells and mice. C59 inhibits PORCN activity in vitro at nanomolar concentrations, as assessed by inhibition of Wnt palmitoylation, Wnt interaction with the carrier protein Wntless/WLS, Wnt secretion, and Wnt activation of β-catenin reporter activity. In mice, C59 displayed good bioavailability, as once daily oral administration was sufficient to maintain blood concentrations well above the IC(50). C59 blocked progression of mammary tumors in MMTV-WNT1 transgenic mice while downregulating Wnt/β-catenin target genes. Surprisingly, mice exhibit no apparent toxicity, such that at a therapeutically effective dose there were no pathologic changes in the gut or other tissues. These results offer preclinical proof-of-concept that inhibiting mammalian Wnts can be achieved by targeting PORCN with small-molecule inhibitors such as C59, and that this is a safe and feasible strategy in vivo.

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

January 15, 2013

Volume

73

Issue

2

Start / End Page

502 / 507

Location

United States

Related Subject Headings

  • beta Catenin
  • Wnt Signaling Pathway
  • Wnt Proteins
  • Pyridines
  • Oncology & Carcinogenesis
  • Mice
  • Membrane Proteins
  • Humans
  • Cell Line, Tumor
  • Breast Neoplasms
 

Citation

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Proffitt, K. D., Madan, B., Ke, Z., Pendharkar, V., Ding, L., Lee, M. A., … Virshup, D. M. (2013). Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer. Cancer Res, 73(2), 502–507. https://doi.org/10.1158/0008-5472.CAN-12-2258
Proffitt, Kyle David, Babita Madan, Zhiyuan Ke, Vishal Pendharkar, Lijun Ding, May Ann Lee, Rami N. Hannoush, and David M. Virshup. “Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer.Cancer Res 73, no. 2 (January 15, 2013): 502–7. https://doi.org/10.1158/0008-5472.CAN-12-2258.
Proffitt KD, Madan B, Ke Z, Pendharkar V, Ding L, Lee MA, et al. Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer. Cancer Res. 2013 Jan 15;73(2):502–7.
Proffitt, Kyle David, et al. “Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer.Cancer Res, vol. 73, no. 2, Jan. 2013, pp. 502–07. Pubmed, doi:10.1158/0008-5472.CAN-12-2258.
Proffitt KD, Madan B, Ke Z, Pendharkar V, Ding L, Lee MA, Hannoush RN, Virshup DM. Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer. Cancer Res. 2013 Jan 15;73(2):502–507.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

January 15, 2013

Volume

73

Issue

2

Start / End Page

502 / 507

Location

United States

Related Subject Headings

  • beta Catenin
  • Wnt Signaling Pathway
  • Wnt Proteins
  • Pyridines
  • Oncology & Carcinogenesis
  • Mice
  • Membrane Proteins
  • Humans
  • Cell Line, Tumor
  • Breast Neoplasms