A small molecule inhibitor of atypical protein kinase C signaling inhibits pancreatic cancer cell transformed growth and invasion

Amanda M. Butler, Michele L. Scotti Buzhardt, Eda Erdogan, Shuhua Li, Kristin S. Inman, Alan P Fields, Nicole R Murray

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Pancreatic cancer is highly resistant to current chemotherapies. Identification of the critical signaling pathways that mediate pancreatic cancer transformed growth is necessary for the development of more effective therapeutic treatments. Recently, we demonstrated that protein kinase C iota (PKCι) and zeta (PKCζ) promote pancreatic cancer transformed growth and invasion, by activating Rac1→ERK and STAT3 signaling pathways, respectively. However, a key question is whether PKCι and PKCζ play redundant (or non-redundant) roles in pancreatic cancer cell transformed growth. Here we describe the novel observations that 1) PKCι and PKCζ are non-redundant in the context of the transformed growth of pancreatic cancer cells; 2) a gold-containing small molecule known to disrupt the PKCι/Par6 interaction, aurothiomalate, also disrupts PKCι/Par6 interaction; 3) aurothiomalate inhibits downstream signaling of both PKCι and PKCζ, and blocks transformed growth of pancreatic cancer cells in vitro; and 4) aurothiomalate inhibits pancreatic cancer tumor growth and metastasis in vivo. Taken together, these data provide convincing evidence that an inhibitor of atypical PKC signaling inhibits two key oncogenic signaling pathways, driven non-redundantly by PKCι and PKCζ, to significantly reduce tumor growth and metastasis. Our results demonstrate that inhibition of atypical PKC signaling is a promising therapeutic strategy to treat pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)15297-15310
Number of pages14
JournalOncotarget
Volume6
Issue number17
StatePublished - 2015

Fingerprint

Pancreatic Neoplasms
Growth
Gold Sodium Thiomalate
PKC-3 protein
protein kinase C lambda
Neoplasm Metastasis
Critical Pathways
Gold
Neoplasms
Therapeutics

Keywords

  • Atypical PKCs
  • Aurothiomalate
  • Invasion
  • Pancreatic cancer
  • Transformed growth

ASJC Scopus subject areas

  • Oncology

Cite this

A small molecule inhibitor of atypical protein kinase C signaling inhibits pancreatic cancer cell transformed growth and invasion. / Butler, Amanda M.; Scotti Buzhardt, Michele L.; Erdogan, Eda; Li, Shuhua; Inman, Kristin S.; Fields, Alan P; Murray, Nicole R.

In: Oncotarget, Vol. 6, No. 17, 2015, p. 15297-15310.

Research output: Contribution to journalArticle

Butler, Amanda M. ; Scotti Buzhardt, Michele L. ; Erdogan, Eda ; Li, Shuhua ; Inman, Kristin S. ; Fields, Alan P ; Murray, Nicole R. / A small molecule inhibitor of atypical protein kinase C signaling inhibits pancreatic cancer cell transformed growth and invasion. In: Oncotarget. 2015 ; Vol. 6, No. 17. pp. 15297-15310.
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