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Scientific Background - Cancer

PI 3-Kinase

The PI3K pathway regulates cellular processes such as proliferation, growth, apoptosis, and cytoskeletal rearrangement. The PI3Ks are heterodimeric lipid kinases that are composed of a regulatory and catalytic subunit that are encoded by different genes. The isoforms offer attractive selectivity and specificity as drug targets (see table). PI3K is activated by activation of growth factor receptor protein tyrosine kinases (RTK), integrin-dependent cell adhesion, and GPCRs.

PI3K activity leads to cellular levels of the lipid marker phosphatidylinositol 3,4,5 trisphosphate or PI(3,4,5)P3 or PIP3 for incipient aggressive metastatic disease.

Normal cellular levels of PIP3 are very low. However, in response to events such as growth factor stimulation, tyrosine kinase receptors activate PI3K to catalyze the formation of PIP3 via phosphorylation of PI(4,5)P2. By increasing cellular levels of PIP3, PI3K induces the formation of defined molecular complexes that act in signal transduction pathways. Most notably, PI3K activity suppresses apoptosis and promotes cell survival through activation of its downstream target, PKB/Akt. PIP3-regulated signaling is governed both by its formation by PI3K and by its conversion into phosphoinositide diphosphates, such as PI(4,5)P2 or PI(3,4)P2. Normally, a rapid spike in cellular PIP3 levels occurs following cellular stimulation, but this is a transient effect, and PIP3 levels return to their normal, low levels within minutes.

Research shows that errors in metabolism that cause enhanced levels of PIP3 can lead to metastatic cancer. The enzyme PI3K produces PIP3.

Research shows that errors in metabolism that cause enhanced levels of PIP3 can lead to metastatic cancer. The enzyme PI3K produces PIP3.

SHIP

The phosphatase SHIP also acts as a negative regulator of PKB/Akt activity. Loss of SHIP activity is one characteristic of chronic myelogenous leukemia providing additional evidence linking the loss of regulation of PIP3 levels with an abnormal proliferative cell state.

PTEN

PTEN (phosphatase and tensin homolog deleted on chromosome ten), also designated MMAC1 (mutated in multiple advanced cancers), is a 3’ phosphatase that converts PIP3 to PI(4,5)P2. PTEN acts as a negative regulator of PKB/Akt activation by PI3K. Loss of PTEN activity results in accumulation of PIP3, abnormal activation of PKB/Akt and suppression of apoptosis, and increased tumor growth and angiogenesis. These are considered to be the primary mechanisms by which PTEN mutations contribute to unregulated growth, carcinogenesis, and tumor progression. Discouraging apoptosis in the cancerous state would not be an effect sought

Lysophosphatidic Acid (LPA) in ovarian cancer

KEY: LPA: lysophosphatidic acid
LPC: lysophosphatidylcholine
LPLD: lysophospholipase D

MG: monoacylglycerol
Edg: Endothelial cell differentiation gene

LPA is a simple lipid produced either extracellularly or intracellularly in response to various growth factors. It is a potent signaling molecule. LPA and S1P signal through specific cell surface receptors of the endothelial cell differentiation gene (Edg) family of GPCRs. LPA is a key mediator in the regulation of cell proliferation, in particular through its effects on drug sensitivity and cell invasiveness in ovarian cancer. Cancers including ovarian, prostate, and breast appear to be modulated by LPA. The recent demonstration that lysoPLD, a proximal enzyme in the production of LPA, is identical to the autocrine motility factor autotoxin (ATX), has provided additional evidence that LPA is a major player in the pathophysiology of cancer. ATX/lysoPLD is upregulated in multiple cancer lineages including non-small cell lung cancer, renal cell carcinoma, glioma, breast cancer, and hepatocellular carcinoma further implicating LPA in tumorigenesis. This strongly suggests that production, metabolism, and molecular sites of action of LPA are important potential targets for cancer therapy.

Hyaluronic Acid (HA) as a marker for Bladder Cancer

Recent publications have shown a correlation between hyaluronic acid urine concentration and bladder cancer. Echelon’s Hyaluronic Acid ELISA kit is able to detect HA levels in urine. HA serum levels have been shown to correlate with Liver disease state. Ref: HYAL1 hyaluronidase: a molecular determinant of bladder tumor growth and invasion. Lokeshwar VB, Cerwinka WH, Lokeshwar BL, Cancer Res. 2005 Mar 15;65(6):2243-50.

assay and reagents for drug discovery in lipid signaling pathways