CD44 Variant Isoforms in Head and Neck Dysplastic Lesions. Part 2
One of the key downstream molecular effectors in EGFR-mediated cell survival is PI-3 kinase. PI-3 kinase is capable of catalyzing the conversion of phosphatidylinositol-3,4-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3), which subsequently results in the activation of AKT. AKT has 3 subtypes: AKT-1, AKT-2, and AKT-3. HA/CD44 signaling in HNSCC activates all three AKT subtypes. Activated AKT down-regulates the cell’s apoptotic potential, thus promoting increased proliferation and tumor cell survival. Torre et al reported that HA/CD44 interaction increased PI-3 kinase activity in HNSCC cells; HA also promoted PI-3 kinase-mediated AKT phosphorylation, resulting in increased tumor cell survival.
CD44-EGFR Signaling and Chemoresistance
HA/CD44 signaling not only appears to promote EGFR-mediated prosurvival effects, but also leads to increased chemoresistance in HNSCC through EGFR signaling pathways. Cisplatin is the most common anticancer drug used today for the treatment of HNSCC. Wang et al reported that HA can promote cisplatin resistance in several HNSCC cell lines; however, the HA-mediated cisplatin resistance could be abolished with inhibitors of EGFR and MAPK.38 The mechanism of action of cisplatin is thought to involve apoptosis-induced cell death. Because AKT suppresses apoptosis, its activation by PI-3 kinase has been suggested to play a key role in cisplatin resistance. Torre et al39 demonstrated that LY-294002, an inhibitor of PI-3 kinase, was capable of blocking HA-mediated cisplatin resistance. Taken together, these reports suggest that HA/CD44 can promote cisplatin resistance in HNSCC through EGFR signaling pathways.
Interaction of HA and CD44 Promotes Cytoskeleton Activation, Migration, Invasion, and Chemoresistance Pathways in HNSCC
A hallmark of all solid malignancies is the ability to invade and/or metastasize to distant sites. Tumor cells possess altered signaling pathwaysthat lead to cytoskeleton activation and migration. Additionally, tumor cells secrete extracellular factors, such as matrix metalloproteinases, to allow breakdown and invasion of the surrounding ECM. Both HA, which is a major component of the ECM, and its major ligand receptor, CD44, have been studied for their role in promoting tumor progression properties, including migration and invasion. The mechanisms of how HA and CD44 interact to promote cytoskeleton activation, migration, and invasion were initially elucidated in several cancer and noncancer models.
RhoA signaling appears to be a critical pathway through which HA/CD44 interaction mediates cytoskeleton activation. One of several important mechanisms used by RhoA in the regulation of cellular functions is through alteration of intracellular Ca2+ levels. Phospholipase C (PLC) is a key mediator in intracellular Ca2+ mobilization. When activated by RhoA, PLCs first hydrolyze PIP2 into inositol trisphosphate (IP3), resulting in Ca2+ release from intracellular stores. This Ca2+ release promotes various cell functions, including cytoskeleton activation, cell cycle progression, and proliferation. Another key RhoA pathway effector is Rho kinase (ROK), which has been shown to regulate several cytoskeletal proteins (such as myosin light chain phosphatase) that are highly involved in tumor migration and to promote the secretion of MMPs, which degrade the ECM during tumor invasion.
HA/CD44 interaction has been shown to be tightly coupled with intracellular Ca2+ mobilization pathways and with RhoA pathways in many different cells. CD44 and RhoA are physically associated in metastatic breast cancer cells, and ROK was found to play a key role in CD44-ankyrin interaction and in RhoA-mediated breast cancer oncogenic signaling. In endothelial cells, HA treatment promoted CD44 interaction with ROK, leading to IP3 receptor-mediated Ca2+ mobilization and migration.9 In keratinocytes, HA-mediated Ca2+ mobilization promoted cortactin-cytoskeleton function, leading to adhesion and differentiation.44 CD44 is linked to ankyrin and has been shown to activate MMP-9 during active migration processes in metastatic breast cancer cells.