title: The Src-family kinase inhibitor PP2 rescues inducible differentiation events in emergent retinoic acid-resistant myeloblastic leukemia cells.
abstract: Retinoic acid is an embryonic morphogen and dietary factor that demonstrates chemotherapeutic efficacy in inducing maturation in leukemia cells. Using HL60 model human myeloid leukemia cells, where all-trans retinoic acid (RA) induces granulocytic differentiation, we developed two emergent RA-resistant HL60 cell lines which are characterized by loss of RA-inducible G1/G0 arrest, CD11b expression, inducible oxidative metabolism and p47(phox) expression. However, RA-treated RA-resistant HL60 continue to exhibit sustained MEK/ERK activation, and one of the two sequentially emergent resistant lines retains RA-inducible CD38 expression. Other signaling events that define the wild-type (WT) response are compromised, including c-Raf phosphorylation and increased expression of c-Cbl, Vav1, and the Src-family kinases (SFKs) Lyn and Fgr. As shown previously in WT HL60 cells, we found that the SFK inhibitor PP2 significantly increases G1/G0 cell cycle arrest, CD38 and CD11b expression, c-Raf phosphorylation and expression of the aforementioned regulators in RA-resistant HL60. The resistant cells were potentially incapable of developing inducible oxidative metabolism. These results motivate the concept that RA resistance can occur in steps, wherein growth arrest and other differentiation events may be recovered in both emergent lines. Investigating the mechanistic anomalies in resistant cell lines is of therapeutic significance and helps to mechanistically understand the response to retinoic acid's biological effects in WT HL60 cells.
authors.affiliation: School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, USA.
authors.forename: Holly A
authors.initials: HA
authors.lastname: Jensen
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Styskal
authors.forename: Ryan
authors.initials: R
authors.lastname: Tasseff
authors.forename: Rodica P
authors.initials: RP
authors.lastname: Bunaciu
authors.forename: Johanna
authors.initials: J
authors.lastname: Congleton
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Varner
authors.forename: Andrew
authors.initials: A
authors.lastname: Yen
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000096:biosynthesis; D000970:Antineoplastic Agents; D039481:CD11b Antigen / Q000096:biosynthesis; D002454:Cell Differentiation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D019255:NADPH Oxidases / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D014212:Tretinoin; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C412373:AG 1879; D000970:Antineoplastic Agents; D039481:CD11b Antigen; C509295:ITGAM protein, human; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D011743:Pyrimidines; C496618:VAV1 protein, human; D014212:Tretinoin; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D050721:Proto-Oncogene Proteins c-cbl; C060902:lyn protein-tyrosine kinase; C053102:proto-oncogene proteins c-fgr; D019061:src-Family Kinases; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; C067419:CBL protein, human
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