Poly(A) polymerase specifically implicated in the mechanism of chemotherapeutic drug action during cell apoptosis

It has recently been established that most anticancer drugs act through the mechanism of apoptosis. It has also been clinically confirmed that drug co mbinations are more effective than single drugs and various chemotherapeuti c strategies have therefore been developed. The experiments described here concern the induction of apoptosis with dimethylsulfoxide (DMSO), a substan ce with multiple activity especially as an inducer of differentiation, and interferon (IFN), a cytokine well known for its antiviral and antineoplasti c effects; they are used alone or in combination. Apoptosis may be regulate d at all levels of gene expression including the addition of the poly(A) ta il to the 3' end of mRNAs. Poly(A) polymerase (PAP) [EC.2.7.7.19], the enzy me that catalyzes the addition of the poly(A) tail to mRNAs, changes in the process of development, differentiation, transformation and apoptosis. In the present study the induction of HeLa cells to apoptosis (65%) with a DMS O/rIFN-alpha combination resulted in pronounced PAP dephosphorylation and a ctivity reduction. HeLa cells induced to apoptosis (35%) with DMSO gave low er levels of PAP dephosphorylation and reduction of activity and cells indu ced to apoptosis (18%) with rIFN-alpha gave only limited PAP dephosphorylat ion and reduction of activity, The implications of these observations for c hemotherapeutic drug action at the level of mRNA polyadenylation point to t he possible use of PAP as a biological marker for the evaluation of this ac tion.