Protein Phosphatase 4 (Pp4) As A Potential Therapeutic Target Gene For Braf Wild Type Melanoma

Protein phosphatase 4 (PP4) participates in cell cycle progression and regulation of centrosome maturation. Gene expression of PP4 is elevated in cancerous tissues of various origins and its overexpression in pancreatic cancer is of prognostic importance. Microarray analysis from primary and metastatic melanoma tissues (N=89) showed that PP4 mRNA expression was up-regulated in metastatic melanoma as compared to primary melanoma of any thickness (relative expression: 1.12 ±0.14, p 2 mm), and varied for the site of metastases from lungu003e intestineu003e skin and subcutaneous tissue. Human melanoma cell lines also demonstrate PP4 gene expression with variable levels. We hypothesized that PP4 may be a novel target for treatment of metastatic melanoma through a BRAF and MEK independent pathway. We performed western blot analysis of human melanoma cell lines: M275 (BRAF wild-type) that had a high level of PP4 gene expression and demonstrated its resistant to BRAF inhibitor (PLX4032) and MEK inhibitor (MEK162) treatment. M275 were chosen for PP4 siRNA gene silencing because of its high level of PP4 protein expression. PP4 protein level was reduced by 20% and 60%, respectively in this cell line at day 4 and 6, respectively; and PP4 siRNA gene silencing reduced cell proliferation by 19.9% and 63.6%. Flow cytometry demonstrated there was higher percentage of apoptotic cells after PP4 siRNA gene silencing as compared to controls (54.4% vs. 15.5%, p, 0.05). PP4 is overexpressed in melanoma as it advances from the skin primary to metastases, and varies to the site of the metastases. We demonstrated that PP4 gene silencing leads to cell cycle arrest and apoptosis. PP4 may be a novel target for BRAF wild type melanoma. Note: This abstract was not presented at the conference. Citation Format: Richard Essner, Ke Wei Gong, David Kaufman, Hsiaowang Chen, Charles Ginther, Judy Dering, Erika von Euw, Bartosz Chmielowski, Richard Finn, Dennis Slamon. Protein phosphatase 4 (PP4) as a potential therapeutic target gene for BRAF wild type melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr A26.