Cancer Stem Cells: From an Insight into the Basics to Recent Advances and Therapeutic Targeting

Figure 6

Signaling pathways involved in cancer stem cells. (a) The NF-κB pathway (left): TNF-α, the proinflammatory cytokine, binds to the TNF receptor and induces the formation of IKK complex, which phosphorylates IκB-a. Phosphorylation of IκB-a results in its degradation via proteasome which leads to the accumulation of p65-p50 (acting as an NF-κB) dimer into the nucleus and regulates the transcription of the targeted genes. (b) The TGF-β pathway (middle): TGFβ1 ligand upon binding to the TGF-beta receptor type-2 (TGFβR2) promotes (indicated by black arrows) the dimerization of TGFβR2 with TGFβR1, resulting in the transphosphorylation of TGFβR1. The activated TGFβR1 further activates R-SMADs (SMAD2 and SMAD3) by phosphorylation. SMAD2/3 trimerizes with a co-SMAD (SMAD4). The SMAD trimer upon localization into the nucleus activates (indicated by purple arrows) the gene transcription and promotes cell growth and survival. (c) The PI3K pathway (right): the binding of the ligand to the RTK results in the phosphorylation of the membrane lipid PIP₂ via intracellular PI3K and it then converts to PIP₃. PKB bounds to its docking site in PIP₃, and upon phosphorylation, it gets activated by various kinases involving mTOR and DNA-dependent protein kinases, which further enhances PKB-mediated phosphorylation and the activation or repression of downstream mediators. PTEN, a phosphatase that is a negative regulator (inhibition is indicated by red arrows) of this process, helps in the dephosphorylation of PIP₃ to PIP₂ (the black arrows are depicting pathway activation/signal propagation).