Protein Kinase Cι Is Required for Pancreatic Cancer Cell Transformed Growth and Tumorigenesis

Abstract

Pancreatic cancer is the fourth leading cause of cancer deaths in the United States, with an overall 5-year survival rate of <5%. Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is highly resistant to conventional chemotherapies, underscoring the critical need for new molecular targets for pancreatic cancer chemotherapy. The KRAS proto-oncogene is mutated in >90% of PDAC. Protein kinase Cι (PKCι) is required for the oncogenic Ras-mediated transformed growth of lung cancer and intestinal epithelial cells. However, little is known about the role of PKCι in pancreatic cancer. In this study, we evaluated the expression of PKCι in human pancreatic cancer and the requirement for PKCι for the transformed growth and tumorigenicity of PDAC cells. We find that PKCι is significantly overexpressed in human pancreatic cancer, and high PKCι expression correlates with poor patient survival. Inhibition of PKCι expression blocks PDAC cell transformed growth in vitro and tumorigenicity in vivo. Inhibition of PKCι expression in pancreatic tumors also significantly reduces tumor angiogenesis and metastasis. Analysis of downstream PKCι effectors implicates the Rac1-MEK/ERK1/2 signaling axis in PKCι-mediated transformed growth and cellular invasion. Taken together, our data show a required role for PKCι in the transformed growth of pancreatic cancer cells and reveal a novel role for PKCι in pancreatic cancer cell metastasis and angiogenesis in vivo. Our results strongly indicate that PKCι will be an effective target for pancreatic cancer therapy. Cancer Res; 70(5); 2064-74. ©2010 AACR.

Repression of cancer cell senescence by PKCι

“…RNA interference RNA duplexes with the following sense strand sequences were used to target PKCi: duplex-A, 5 0 -GTGCATCAACTGCAAA CTC-3 0 (Baldwin et al, 2006); duplex-C, 5 0 -CTTCCTGAAGA ACATGCCA-3 0 (Xu and Deng, 2006); duplex-E, 5 0 -GCCTG GATACAATTAACCATT-3 0 (Scotti et al, 2010). Sense strand sequences of RNA duplexes targeting p21 were as follows: duplex-B, 5 0 -GCCTTAGTCTCAGTTTGTGTG; duplex-C, 5 0 -GATGGAACTTCGACTTTGT.…”

PKCλ/ι signaling promotes triple-negative breast cancer growth and metastasis

“…10,11 Importantly, the PKCl/i gene is located at the 3q26.2 genomic region, which is most frequently amplified in human cancer 16,17 , and overexpression of PKCl/i has been implicated in cancer development in multiple tissues including the lung, 18,19 pancreas, 20 stomach, 21 colon, 22 esophagus, 23 liver, 24 bile duct, 25 ovary, 17 prostate 26 and brain. 27 Recently, few studies have been reported higher expression of PKCl/i in ER/PRand HER-positive breast cancer and also in lymph node metastases.…”

PRKCI (protein kinase C, iota)

“…Note PKCι overexpression has been observed in numerous human cancers including cancers of the lung (Regala et al, 2005b), pancreas (Scotti et al, 2010), stomach (Takagawa et al, 2010), colon (Murray et al, 2004), esophagus (Yang et al, 2008), liver (Du et al, 2009), bile duct (Li et al, 2008), breast (Kojima et al, 2008), ovary (Weichert et al, 2003;Eder et al, 2005;Zhang et al, 2006), prostate (Ishiguro et al, 2009), and brain (Patel et al, 2008). PKCι is itself an oncogene, which appears to be activated through tumor-specific overexpression.…”

“…PKCι overexpression predicts poor survival in pancreatic cancer patients (Scotti et al, 2010). Oncogenesis PKCι is significantly overexpressed in human pancreatic cancer.…”