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Estrogen promotes and testosterone inhibits tumorigenesis and metastasis associated with ADP-ribosyl-acceptor hydrolase 1 (ARH1)-deficiency

Thursday, September 17, 2015 — Poster Session II

12:00 p.m. – 1:30 p.m.
FAES Terrace
NHLBI
CANCER-15

Authors

  • J Kato
  • X Bu
  • J Moss

Abstract

ADP-ribosylation, a reaction in which the ADP-ribose moiety of NAD is transferred to acceptors is used by bacterial toxins to disrupt cell function. In mammalian cells, ADP-ribosylation is regulated by ADP-ribosyltransferases (ARTs) that transfer ADP-ribose, and ADP-ribose-acceptor hydrolases (ARHs) that cleave the ADP-ribose-acceptor bond. ARH1 preferentially hydrolyzes ADP-ribose(arginine) proteins. We reported previously that tumor formation and metastases (e.g., adenocarcinomas, lymphomas) exhibited a significant gender effect. Female ARH1-/- and ARH1+/- mice developed single and multiple tumors as well as metastasis more frequently and at a younger age than their male counterparts. Further, estrogen promoted tumorigenesis in nude mice and the survival of ARH1-/- mouse embryonic fibroblasts (MEFs) in the circulation. In this report, we examine the effects of testosterone. Nude mice were supplemented with 17-β-estradiol [E2] and/or testosterone and then were injected with ARH1-/- MEFs subcutaneously and intravenously. Subcutaneous tumor growth in female or female ovariectomized (FO) nude mice supplemented with both testosterone and E2 (FET or FOET) was significantly slower than that seen in female or FO nude mice supplemented with E2 (FE or FOE) alone. Also, size of pulmonary metastases following intravenous injection of ARH1-/- MEFs in testosterone (T) and E2 groups (FET, FOET and MET) was smaller than those in E2 groups (FE, FOE and ME). Thus, testosterone inhibited estrogen effects on tumor growth. Estrogen enhanced and testosterone inhibited tumor development and growth as well as pulmonary metastasis. Our data demonstrate that gender plays an important role in tumor formation and metastases secondary to ARH1 deficiency.

Category: Cancer Biology