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GRK2 promotes growth of medulloblastoma cells and protects them from chemotherapy-induced apoptosis.

ABSTRACT: G-protein coupled receptor kinase 2 (GRK2; ADRBK1, BARK1) is most known as a regulator of G-protein coupled receptors. However, GRK2 also has other functions. Medulloblastomas are the most common malignant brain cancers in children. GRK2 has not been implicated in medulloblastoma biology. Here we report that GRK2 knockdown slowed cell growth, diminished proliferation, and enhanced cisplatin- and etoposide-induced apoptosis in medulloblastoma cell lines UW228-2 and Daoy. Reciprocally, GRK2 overexpression attenuated apoptosis induced by these chemotherapy drugs. Cisplatin and etoposide increased phosphorylation of AKT (S473) and GRK2 knockdown mitigated this increase. Cisplatin and etoposide attenuated ERK phosphorylation, but GRK2 knockdown did not alter this effect. Wildtype GRK2 reversed the increase in cisplatin- and etoposide-induced apoptosis caused by GRK2 knockdown. GRK2-K220R (kinase dead) and GRK2-S670A (unphosphorylated, constitutively active) conferred protection from cisplatin that was similar to wildtype GRK2, suggesting that this protection may be mediated though a kinase-independent activity of GRK2. These data demonstrate that GRK2 contributes to proliferation and survival of these medulloblastoma cell lines and to their protection from cisplatin- and etoposide-induced apoptosis.

SUBMITTER: Pathania AS

PROVIDER: S-EPMC6761358 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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GRK2 promotes growth of medulloblastoma cells and protects them from chemotherapy-induced apoptosis.

Pathania Anup S AS Ren Xiuhai X Mahdi Min Y MY Shackleford Gregory M GM Erdreich-Epstein Anat A

Scientific reports 20190925 1

G-protein coupled receptor kinase 2 (GRK2; ADRBK1, BARK1) is most known as a regulator of G-protein coupled receptors. However, GRK2 also has other functions. Medulloblastomas are the most common malignant brain cancers in children. GRK2 has not been implicated in medulloblastoma biology. Here we report that GRK2 knockdown slowed cell growth, diminished proliferation, and enhanced cisplatin- and etoposide-induced apoptosis in medulloblastoma cell lines UW228-2 and Daoy. Reciprocally, GRK2 overex ...[more]

PMID: 31554835

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Project description:BACKGROUND & AIMS:Helicobacter pylori infection disrupts the balance between gastric epithelial cell proliferation and apoptosis, which is likely to lower the threshold for the development of gastric adenocarcinoma. H pylori infection is associated with epidermal growth factor (EGF) receptor (EGFR) activation through metalloproteinase-dependent release of EGFR ligands in gastric epithelial cells. Because EGFR signaling regulates cell survival, we investigated whether activation of EGFR following H pylori infection promotes gastric epithelial survival. METHODS:Mouse conditionally immortalized stomach epithelial cells (ImSt) and a human gastric epithelial cell line, AGS cells, as well as wild-type and kinase-defective EGFR (EGFRwa2) mice, were infected with the H pylori cag+ strain 7.13. Apoptosis, caspase activity, EGFR activation (phosphorylation), and EGFR downstream targets were analyzed. RESULTS:Inhibiting EGFR kinase activity or decreasing EGFR expression significantly increased H pylori-induced apoptosis in ImSt. Blocking H pylori-induced EGFR activation with a heparin-binding (HB)-EGF neutralizing antibody or abrogating a disintegrin and matrix metalloproteinase-17 (ADAM-17) expression increased apoptosis of H pylori-infected AGS and ImSt, respectively. Conversely, pretreatment of ImSt with HB-EGF completely blocked H pylori-induced apoptosis. H pylori infection stimulated gastric epithelial cell apoptosis in EGFRwa2 but not in wild-type mice. Furthermore, H pylori-induced EGFR phosphorylation stimulated phosphotidylinositol-3'-kinase-dependent activation of the antiapoptotic factor Akt, increased expression of the antiapoptotic factor Bcl-2, and decreased expression of the proapoptotic factor Bax. CONCLUSIONS:EGFR activation by H pylori infection has an antiapoptotic effect in gastric epithelial cells that appears to involve Akt signaling and Bcl family members. These findings provide important insights into the mechanisms of H pylori-associated tumorigenesis.

Project description:The effects and underlying mechanisms of butyrate and butyrate+niacin on apoptosis in sheep rumen epithelial cells were investigated. Cells were exposed to butyrate (0-140?mM) for 6?h. A low concentration (20?mM) of butyrate increased cell viability and promoted growth whereas high concentrations (40-140?mM) inhibited proliferation. Cells were then cocultured with 120?mM butyrate and niacin (0-100?mM) for 6?h. Niacin addition attenuated butyrate-induced cellular damage and promoted proliferation at 20-80?mM; 40?mM presented the optimal effect. Higher concentrations (100?mM) of niacin resulted in low cell viability. Subsequent experiments confirmed that 120?mM butyrate increased intracellular reactive oxygen species (ROS) production and reduced the intracellular total antioxidant capacity (T-AOC) versus the untreated control. Compared with 120?mM butyrate, cotreatment with 40?mM niacin significantly reduced the intracellular ROS content and increased the intracellular T-AOC. Flow cytometry analysis revealed that 120?mM butyrate increased the proportion of apoptotic cells by 17.8% versus the untreated control, and 120?mM butyrate+40?mM niacin treatment reduced the proportion of apoptotic cells by 28.6% and 39.4% versus the untreated control and butyrate treatment, respectively. Treatment with 120?mM butyrate increased caspase-9 and p53 mRNA levels and decreased the expression of Bcl-2 and Bax, and the Bcl-2/Bax ratio versus the untreated control. Treatment with 120?mM butyrate+40?mM niacin downregulated the expression of caspase-3 and p53 and increased the expression of Bcl-2 and Bax versus butyrate treatment alone but had no effect on the Bcl-2/Bax ratio. Thus, high concentrations of butyrate may induce rumen epithelial cell apoptosis by increasing oxidative stress and inducing caspase-9 and p53 expression. Cotreatment with niacin regulates apoptosis-related gene expression by reducing intracellular ROS production and DNA damage and downregulating caspase-3 and p53 expressions to protect rumen epithelial cells against butyrate-induced apoptosis.

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GRK2 promotes growth of medulloblastoma cells and protects them from chemotherapy-induced apoptosis.

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GRK2 promotes growth of medulloblastoma cells and protects them from chemotherapy-induced apoptosis.

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