Chapter 080. Cancer Cell Biology and Angiogenesis (Part 8)

PI3K is a heterodimeric lipid kinase that catalyses the conversion of phosphatidylinositol bisphosphate (PIP2) to phosphatidylinositol trisphosphate (PIP3), which acts as a plasma membrane docking site for proteins that contain a pleckstrin homology (PH) domain. These include the serine/threonine kinases Akt and PDK1 that are key downstream effectors of PI3K action (Fig. 80-2). The PI3K pathway is activated in 30–40% of human cancers and is thought to play a critical role in tumor cell survival, proliferation, growth, and glucose utilization. Amplification or activating point mutation of the gene encoding the catalytic subunit of PI3K (p110) is observed in 20–30%...
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Chapter 080. Cancer Cell Biology and Angiogenesis (Part 8) Chapter 080. Cancer Cell Biology and Angiogenesis (Part 8) PI3K is a heterodimeric lipid kinase that catalyses the conversion ofphosphatidylinositol bisphosphate (PIP2) to phosphatidylinositol trisphosphate(PIP3), which acts as a plasma membrane docking site for proteins that contain apleckstrin homology (PH) domain. These include the serine/threonine kinases Aktand PDK1 that are key downstream effectors of PI3K action (Fig. 80-2). The PI3Kpathway is activated in 30–40% of human cancers and is thought to play a criticalrole in tumor cell survival, proliferation, growth, and glucose utilization.Amplification or activating point mutation of the gene encoding the catalyticsubunit of PI3K (p110) is observed in 20–30% of breast, colon, brain, gastric, andovarian cancers, and amplification of the Akt2 gene occurs in breast, ovarian, andpancreatic cancers. The tumor suppressor PTEN (phosphatase with tensinhomology), a lipid phosphatase that acts as an off signal for PI3K bydephosphorylating PIP3, is mutated in many human cancers, leading to uncheckedactivity of the PI3K pathway. Akt promotes cell survival by activation of thetranscription factor nuclear factor of κB (NFκB); it also enhances cell cycleprogression by inhibition of glycogen synthetase kinase 3β (GSK3β) and FOXOtranscription factors, thus preventing inactivation of Myc, β-catenin, cyclin D1,and cyclin E, and blocking upregulation of p27 Kip1 and Bim (an apoptosis-inducingprotein). Furthermore, the growth of cancer cells requires the activation of twodownstream kinases, mammalian target of rapamycin (mTOR) and p70S6K,whose activities promote the translation of cellular mRNAs. Targeted interruptionof the PI3K pathway is being attempted at multiple levels. Inhibitors of mTOR,including rapamycin and its more soluble ester derivative temsirolimus (tem),selectively kill human tumor cell lines with PTEN mutations and upregulatedPI3K pathway activity. Early clinical data indicate that tem has activity in renalcell cancer, perhaps by blocking the translation of the transcription factor hypoxia-inducible factor (HIF)-1α mRNA, a mediator of cellular responses to hypoxia,which requires mTOR activity for efficient translation. RTKs activate other signaling pathways. Activation of phospholipase C-γ(PLC) results in the hydrolysis of PIP2 into diacylglycerol (DAG) and IP3. DAGtogether with calcium ion (Ca2+) activates protein kinase C (PKC), a family ofserine/threonine-specific protein kinases with different activation requirements,subcellular locations, and substrates in different cell types. PKC is the target oftumor-promoting phorbol esters, and its activation can modulate cell proliferation,differentiation, and tumorigenesis. The PKC inhibitor bryostatin 1 has reachedphase II clinical trials and thus far has demonstrated only minimal antitumoractivity. However, an antisense oligonucleotide directed against PKC and anumber of small molecule inhibitors that demonstrate greater selectivity for PKCisoforms are undergoing clinical evaluation. Alterations in Gene Transcription in Cancer Cells: Role of EpigeneticChanges Chromatin structure regulates the hierarchical order of sequential genetranscription that governs differentiation and tissue homeostasis. Disruption ofchromatin remodeling leads to aberrant gene expression and can induceproliferation of undifferentiated cells, leading to cancer. Epigenetics is defined aschanges that alter the pattern of gene expression that persist across at least one celldivision, but are not caused by changes in the DNA code. Epigenetic changesinclude alterations of chromatin structure mediated by methylation of cytosineresidues in CpG dinucleotides, modification of histones by acetylation ormethylation, or changes in higher-order chromosome structure (Fig. 80-4). Thetranscriptional regulatory regions of active genes often contain a high frequency ofCpG dinucleotides (referred to as CpG islands), which under normalcircumstances remain unmethylated. Expression of these genes is controlled bytransient association with repressor or activator proteins that regulatetranscriptional activation. However, hypermethylation of promoter regions is acommon mechanism by which tumor-suppressor loci are epigenetically silenced incancer cells. Thus one allele may be inactivated by mutation or deletion (as occursin loss of heterozygosity), while expression of the other allele is epigeneticallysilenced. The mechanisms that target suppressor oncogenes for this form of genesilencing are unknown. Figure 80-4 Epigenetic regulation of gene expression in cancer cells. Tumor-suppressor genes are often epigenetically silenced in ca ...