PT  - JOURNAL ARTICLE
AU  - Clint Mitchell
AU  - Margaret A Park
AU  - Patrick Eulitt
AU  - Chen Yang
AU  - Adly Yacoub
AU  - Paul Dent
TI  - PARP1 modulates the lethality CHK1 inhibitors in carcinoma cells
AID  - 10.1124/mol.110.067199
DP  - 2010 Aug 09
TA  - Molecular Pharmacology
PG  - mol.110.067199
4099  - http://molpharm.aspetjournals.org/content/early/2010/08/09/mol.110.067199.short
4100  - http://molpharm.aspetjournals.org/content/early/2010/08/09/mol.110.067199.full
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.