Stromal cell protection of B-lineage acute lymphoblastic leukemic cells during chemotherapy requires active Akt.
Several studies document ALL cell response to survival signals from bone marrow stromal cells. The current study suggests a requirement for active Akt in ALL cells for optimal stromal cell protection during chemotherapy. ALL cells expressing dominant negative Akt were not efficiently rescued from Ara-C or etoposide-induced apoptosis by stromal cell co-culture. In addition, inhibition of ALL cell PI-3 kinase activity diminished stromal cells support of tumor cells during treatment. ALL cell lines co-cultured with bone marrow stromal cells during chemotherapy maintained higher levels of phosphorylated Akt protein and reduced PP2A activity when compared to ALL cells treated in medium alone. Chemotherapy-induced PARP and Bcl-2 cleavage was reduced in ALL cells cultured with a stromal cell layer compared to tumor cells exposed to drug in medium alone. However, interaction with stromal cells was not able to efficiently block treatment-induced PARP or Bcl-2 cleavage in leukemic cells with blunted Akt activity. These data suggest a pivotal role for Akt in mediating stromal cell regulation of ALL cell apoptosis.
Wang
Lin
L
Department of Pediatrics, West Virginia University School of Medicine, Morgantown, WV, USA.
Fortney
James E
JE
Gibson
Laura F
LF
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000473:pathology*; D002470:Cell Survival; D018920:Coculture Techniques; D003561:Cytarabine / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D051379:Mice; D010749:Phosphoprotein Phosphatases / Q000032:analysis / Q000378:metabolism; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000032:analysis / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000378:metabolism; D017154:Stromal Cells / Q000502:physiology*
D000970:Antineoplastic Agents; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D003561:Cytarabine; D005047:Etoposide; D011065:Poly(ADP-ribose) Polymerases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010749:Phosphoprotein Phosphatases