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

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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) 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% of breast, colon, brain, gastric, and ovarian cancers, and amplification of the Akt2 gene occurs in breast, ovarian, and pancreatic cancers. The tumor suppressor PTEN (phosphatase with tensin homology), a lipid phosphatase that acts as an off signal for PI3K by
dephosphorylating PIP3, is mutated in many human cancers, leading to unchecked activity of the PI3K pathway. Akt promotes cell survival by activation of the transcription factor nuclear factor of κB (NFκB); it also enhances cell cycle progression by inhibition of glycogen synthetase kinase 3β (GSK3β) and FOXO transcription factors, thus preventing inactivation of Myc, β-catenin, cyclin D1, and cyclin E, and blocking upregulation of p27 Kip1 and Bim (an apoptosis-inducing protein). Furthermore, the growth of cancer cells requires the activation of two downstream kinases, mammalian target of rapamycin (mTOR) and p70S6K, whose activities promote the translation of cellular mRNAs. Targeted interruption of 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 upregulated PI3K pathway activity. Early clinical data indicate that tem has activity in renal cell 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. DAG together with calcium ion (Ca2+) activates protein kinase C (PKC), a family of serine/threonine-specific protein kinases with different activation requirements, subcellular locations, and substrates in different cell types. PKC is the target of
tumor-promoting phorbol esters, and its activation can modulate cell proliferation, differentiation, and tumorigenesis. The PKC inhibitor bryostatin 1 has reached phase II clinical trials and thus far has demonstrated only minimal antitumor activity. However, an antisense oligonucleotide directed against PKC and a number of small molecule inhibitors that demonstrate greater selectivity for PKC isoforms are undergoing clinical evaluation. Alterations in Gene Transcription in Cancer Cells: Role of Epigenetic Changes Chromatin structure regulates the hierarchical order of sequential gene transcription that governs differentiation and tissue homeostasis. Disruption of chromatin remodeling leads to aberrant gene expression and can induce proliferation of undifferentiated cells, leading to cancer. Epigenetics is defined as changes that alter the pattern of gene expression that persist across at least one cell division, but are not caused by changes in the DNA code. Epigenetic changes include alterations of chromatin structure mediated by methylation of cytosine residues in CpG dinucleotides, modification of histones by acetylation or methylation, or changes in higher-order chromosome structure (Fig. 80-4). The transcriptional regulatory regions of active genes often contain a high frequency of CpG dinucleotides (referred to as CpG islands), which under normal circumstances remain unmethylated. Expression of these genes is controlled by transient association with repressor or activator proteins that regulate
transcriptional activation. However, hypermethylation of promoter regions is a common mechanism by which tumor-suppressor loci are epigenetically silenced in cancer cells. Thus one allele may be inactivated by mutation or deletion (as occurs in loss of heterozygosity), while expression of the other allele is epigenetically silenced. The mechanisms that target suppressor oncogenes for this form of gene silencing are unknown. Figure 80-4 Epigenetic regulation of gene expression in cancer cells. Tumor- suppressor genes are often epigenetically silenced in cancer cells. In the upper
portion, a CpG island within the promoter and enhancer regions of the gene has been methylated, resulting in the recruitment of methyl-cytosine binding proteins (MeCP) and complexes with histone deacetylase (HDAC) activity. Chromatin is in a condensed, nonpermissive conformation that inhibits transcription. Clinical trials are under way utilizing the combination of demethylating agents such as 5- aza-2'-deoxycytidine plus HDAC inhibitors, which together confer an open, permissive chromatin structure (lower portion). Transcription factors bind to specific DNA sequences in promoter regions and, through protein-protein interactions, recruit coactivator complexes containing histone acetyl transferase (HAT) activity. This enhances transcription initiation by RNA polymerase II and associated general transcription factors. The expression of the tumor-suppressor gene commences, with phenotypic changes that may include growth arrest, differentiation, or apoptosis.