Induction of APOBEC3C facilitates the genotoxic stress-mediated cytotoxicity of artesunate.

Abstract

Artemisinin class of anticancer compounds is well-known for oxidative DNA damage-mediated growth arrest followed by cell death. However, the nature of this genotoxic stress for cancer therapeutics remains elusive. Here, we show that artesunate (Art), a water-soluble artemisinin analog, triggers inducible anticancer responses directly implicated in the DNA damage-intended therapy. We observed that the level of the antiviral enzyme APOBEC3C (apolipoprotein-B mRNA-editing catalytic polypeptide-like 3C, or A3C) preferentially increased upon treatment with Art against tumor xenografts of p53-deficitent H1299 cells. Using gain-of-function experiments, A3C could improve the therapeutic efficacy of Art determined by cell proliferation and colony formation assays. Furthermore, elevated A3C provoked a minor accumulation of γH2AX foci and phosphorylation of RPA32 and Chk1 which strongly sensitized H1299 cells to Art. Employment of A3C also caused increased the synergistic interaction between Art and Chk1 inhibition. Besides, A3C overexpression delayed cell cycle at S phase, accompanied by attenuated G2/M arrest in the presence of Art. Enzymatic inactivation of A3C by mutation of zinc-coordinating residues (C97S and C100S) indicated that A3C sensitized Art in a deaminase-dependent manner. Further, we showed using small interfering RNA against A3C can induce the chemoresistance of Art. These studies combine to suggest that upregulated A3C is involved in Art-induced DNA damage response as a consequent event to improve overall cytotoxic responses of Art.