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

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 PKCζ/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.

PKCι regulates nuclear YAP1 localization and ovarian cancer tumorigenesis

“…Our data establish a novel PKCι-AMOT-YAP1 signaling pathway that drives OSC tumorigenesis and is active in primary OSC tumors. Our finding that ANF, a compound that inhibits oncogenic PKCι signaling, 3, 4, 8, 25, 34 blocks PKCι-YAP1 signaling and inhibits OSC growth in vitro and OSC tumorigenesis in vivo suggests a plausible therapeutic intervention strategy for treatment of OSC. In this regard, we have observed preliminary clinical activity of ANF in ovarian cancer patients in a maintenance setting.…”

“…Treatment of OSC cells with auranofin (ANF), which inhibits PKCι signaling, 4, 25 induced loss of nuclear YAP1 (Fig. 9A).…”

“…It is well-established that PKCζ and PKCι are non-redundant enzymes that play distinct, non-overlapping and often opposing roles in human tumorigenesis. 25, 33–36 In this regard, OSC tumors exhibit low levels of PKCζ, in stark contrast to PKCι, which is overexpressed as a result of 3q26 CNG. Interestingly, PKCι KD did not alter YAP1 phosphorylation, indicating that direct phosphorylation is not a major mechanism by which PKCι regulates YAP1 nuclear function in OSC cells.…”

Protein Kinase Cι Drives a NOTCH3-dependent Stem-like Phenotype in Mutant KRAS Lung Adenocarcinoma

“…GSI inhibitors of NOTCH exhibit potent anti-tumor activity in glioma (Fan et al, 2010; Fan et al, 2006), lung (Konishi et al, 2007), and ovarian cancers (Groeneweg et al, 2014a; Groeneweg et al, 2014b) and the potent GSI PF-03084014 has shown clinical promise in advanced cancer patients (Messersmith et al, 2015). The anti-rheumatoid gold salts ATM and ANF selectively inhibit PKCι signaling and block growth of lung (Erdogan et al, 2006; Fields et al, 2007; Regala et al, 2008; Stallings-Mann et al, 2006), pancreatic (Butler et al, 2015; Scotti et al, 2012) and ovarian (Wang et al, 2013) tumors in vitro and in vivo , and two clinical studies have demonstrated proof-of-principle for PKCι inhibitor-based therapy with ATM (Mansfield et al, 2013) and ANF (Jatoi et al, 2014). Our finding that GSI and ANF exhibit highly synergistic anti-tumor activity suggests a novel therapeutic approach to treat KRAS LADC, a tumor sub-type for which there is a dire need for effective targeted therapeutics.…”

Incorporation and visualization of azido-functionalized N-oleoyl serinol in Jurkat cells, mouse brain astrocytes, 3T3 fibroblasts and human brain microvascular endothelial cells

“…7 aPKC has been also evaluated successfully as a target for small molecule drug candidates against pancreatic cancer cells. 8 Here we present preliminary data on the synthesis and biological studies of 3a and 3b azido analogues of S18. Ceramide analogs with fluorescent tags proved to be useful for the study of dynamics and visualizing membrane architecture.…”