Constitutive levels of cAMP-dependent protein kinase activity determine sensitivity of human multidrug-resistant leukaemic cell lines to growth inhibition and apoptosis by forskolin and tumour necrosis factor alpha

Br J Haematol. 2000 Mar;108(3):565-73. doi: 10.1046/j.1365-2141.2000.01903.x.

Abstract

The cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) signal pathway regulates cell proliferation, differentiation and cell death. It may also regulate the multidrug resistance (MDR) phenotype in leukaemic cells. These data showed that MDR1+ K/Dau600 cells exhibited a higher basal level of PKA activity than MDR- parental cells. The significance of this on tumour necrosis factor alpha (TNFalpha)-induced apoptosis and cytostasis was investigated further. In comparison with MDR1- parental cells, K/Dau600 cells had a higher expression of PKA regulatory subunit RIalpha and nuclear catalytic subunit PKAcalpha. They were also more susceptible to inhibition of proliferation and induction of apoptosis by TNFalpha and/or forskolin, but this could be attenuated by H89. An increase in cAMP was associated with the apoptosis in the K/Dau600 cell line. Forskolin inactivated NF-kappaB in K/Dau600 cells but not in K562 cl. 6 cells, whereas TNF activated NF-kappaB in K562 cl.6 cells but not in K/Dau600 cells. 8-Cl-cAMP exhibited similar inhibitory effects on the proliferation of all of the cell lines used via its metabolite 8-Cl-adenosine, which indicates that these effects were independent of residual PKA or cAMP. Therefore, the differential sensitivity to apoptosis and/or growth inhibition could be mediated via cAMP, partly through PKA via NF-kappaB and partly by PKA-independent pathways.

MeSH terms

  • 8-Bromo Cyclic Adenosine Monophosphate / analogs & derivatives
  • 8-Bromo Cyclic Adenosine Monophosphate / pharmacology
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects*
  • Cell Division / drug effects
  • Colforsin / therapeutic use*
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Isoquinolines / pharmacology
  • Leukemia / drug therapy
  • Leukemia / enzymology*
  • Leukemia / metabolism
  • NF-kappa B / metabolism
  • Sulfonamides*
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / therapeutic use

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Isoquinolines
  • NF-kappa B
  • Sulfonamides
  • Tumor Necrosis Factor-alpha
  • Colforsin
  • 8-Bromo Cyclic Adenosine Monophosphate
  • 8-chloro-cyclic adenosine monophosphate
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide