- Title
- Inositol polyphosphate 4-phosphatase II (INPP4B) promotes P13K signalling and functions as an oncogenic regulator in human colon cancer and melanoma
- Creator
- Chi, Mengna
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2015
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Aberrant activation of survival-signaling pathways causes uncontrolled cell proliferation and resistance to apoptosis, and plays an important role in cancer development, progression, and resistance to treatment (Courtney et al., 2010; Ferte et al., 2010). In colorectal cancer (CRC), activation of the phosphatidylinositol 3-kinase (PI3K) pathway is of particular importance, in that many common genetic and epigenetic anomalies in the disease, such as amplification of epidermal growth factor (EGF) receptor, activating mutations in KRAS, and loss of phosphate and tensin homolog deleted on chromosome 10 (PTEN), converge on activation of PI3K signalling (Colakoglu et al., 2008). Moreover, activating mutations of PIK3CA, the gene encoding the catalytic subunit of PI3K, is found in up to 40% of colon cancers (Colakoglu et al., 2008; De Roock et al., 2011). In melanoma, identification of activating mutations in BRAF as the major cause of constitutive activation of the mitogen activated protein kinase (MAPK) pathway has led to successful development of mutant BRAF-specific inhibitors in the treatment of the disease (Chapman et al., 2011; Davies et al., 2002; Houslay, 2011; Ribas and Flaherty, 2011). However, primary and acquired resistance, which is commonly associated with activation of other survival pathways, in particular, the phosphatidylinositol 3-kinase (PI3K) signaling pathway, remains a major obstacle in the quest for curative treatment (Jiang et al., 2011; Karreth et al., 2011; Paraiso et al., 2011; Poulikakos and Rosen, 2011). Indeed, activation of PI3K signaling has been shown to cooperate with mutant BRAF in melanomagenesis using in vivo models (Cheung et al., 2008; Dankort et al., 2009). Activation of PI3K signaling is negatively regulated by three classes of inositol polyphosphate phosphatases (Fedele et al., 2010; Gewinner et al., 2009; Kisseleva et al., 2002). The inositol polyphosphate 3-phosphatase (3-phosphatase) PTEN dephosphorylates the 3-position of PI(3,4,5)P₃ to generate PI(4,5)P₂ (Carracedo et al., 2011; Ma et al., 2008), whereas 5-phosphatases, such as Src homology 2-containing inositol 5- phosphatase (SHIP) and phosphatidylinositol 4,5-Bisphosphate 5- Phosphatase (PIB5PA)/proline-rich inositol polyphosphate phosphatase (PIPP) dephosphorylate the 5-position to produce PI(3,4)P₂ (Ooms et al., 2006; Ye et al., 2013a). PI(3,4)P₂ is in turn subjected to dephosphorylation by inositol polyphosphate 4-phosphatase type I (INPP4A) and type II (INPP4B) at the 4-position to generate PI(3)P, thus terminating PI3K signaling (Fedele et al., 2010; Gewinner et al., 2009; Hodgson et al., 2011). Interestingly, despite INPP4B tumor suppressive role in some other tissues, in this study we found that inositol polyphosphate 4-phosphatase type II (INPP4B) functions as an oncogenic regulator in human colon cancer and melanoma. While INPP4B is upregulated in two cancers and its high expression is associated with poor patient survival, INPP4B knockdown blocks activation of PI3K downstream signaling, inhibits proliferation, undermines survival of colon cancer and melanoma cells, and retards cancer growth in a xenograft model. Conversely, overexpression of INPP4B causes increased proliferation and anchorage-independent growth in normal colon epithelial cells and melanocytes. However, INPP4B regulates PI3K signalling pathway in two cancers by different mechanisms. It plays an important role for maintaining cellular PI(3,4,5)P₃ and PI(3,4)P₂ levels in colon cancer whereas PI(3)P levels in melanoma cells. Also, the increase in INPP4B is primarily due to Ets-1-mediated transcriptional upregulation in colon cancer cells, whereas a posttranscriptional increase via reduction of miRNA-494 and miRNA-599 in melanoma.
- Subject
- INPP4B; PI3K signalling; pSGK3; pAkt; melanoma; colon cancer
- Identifier
- http://hdl.handle.net/1959.13/1059871
- Identifier
- uon:16707
- Rights
- Copyright 2015 Mengna Chi
- Language
- eng
- Full Text
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