RT Journal Article
SR Electronic
T1 PARP1 modulates the lethality CHK1 inhibitors in carcinoma cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.110.067199
DO 10.1124/mol.110.067199
A1 Clint Mitchell
A1 Margaret A Park
A1 Patrick Eulitt
A1 Chen Yang
A1 Adly Yacoub
A1 Paul Dent
YR 2010
UL http://molpharm.aspetjournals.org/content/early/2010/08/09/mol.110.067199.abstract
AB Prior studies have demonstrated that inhibition of CHK1 can promote activation of ERK1/2 and phosphorylation of histone H2AX, and also that inhibition of PARP1 can impact on growth factor-induced ERK1/2 activation. The present studies were initiated to determine in whether CHK1 inhibitors interacted with PARP1 inhibition to facilitate apoptosis. Transient expression of dominant negative CHK1 raised basal ERK1/2 activity and prevented CHK1 inhibitors from activating ERK1/2. CHK1 inhibitors modestly increased the levels of PARP1 ADP ribosylation and molecular or small molecule inhibition of PARP1 blocked CHK1 inhibitor-stimulated histone H2AX phosphorylation and activation of ERK1/2. Stimulated histone H2AX phosphorylation was ATM dependent. Multiple CHK1 inhibitors interacted in a greater than additive fashion with multiple PARP1 inhibitors to cause transformed cell killing in short term viability assays and synergistically killed tumor cells in colony formation assays. Over-expression of BCL-XL or loss of BAX/BAK function, but not the function of BID, suppressed CHK1 inhibitor + PARP1 inhibitor lethality. Inhibition of BCL-2 family protein function enhanced CHK1 inhibitor + PARP1 inhibitor lethality and restored drug-induced cell killing in cells over-expressing BCL-XL. Thus PARP1 plays an important role in regulating the ability of CHK1 inhibitors to activate ERK1/2 as well as the DNA damage response. An inability of PARP1 to modulate this response results in transformed cell death mediated through the intrinsic apoptosis pathway.