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

The cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) si gnal 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 bas al level of PKA activity than MDR- parental cells. The significance of this on tumour necrosis factor alpha (TNF alpha)-induced apoptosis and cytostas is was investigated further. In comparison with MDR1(-) parental cells, K/D au600 cells had a higher expression of PKA regulatory subunit RI alpha and nuclear catalytic subunit PKAc alpha. They were also more susceptible to in hibition of proliferation and induction of apoptosis by TNF alpha and/or fo rskolin, but this could be attenuated by H89. An increase in cAMP was assoc iated with the apoptosis in the K/Dau600 cell line. Forskolin inactivated N F-kappa B in K/Dau600 cells but not in K562 cl.6 cells, whereas TNF activat ed NF-kappa B in K562 cl.6 cells but not in K/Dau600 cells. 8-Cl-cAMP exhib ited similar inhibitory effects on the proliferation of all of the cell lin es used via its metabolite 8-Cl-adenosine, which indicates that these effec ts were independent of residual PKA or cAMP. Therefore, the differential se nsitivity to apoptosis and/or growth inhibition could be mediated via cAMP, partly through PKA via NF-kappa B and partly by PKA-independent pathways.