Tetraiodothyroacetic acid (tetrac) receptor on integrin αvβ3: tetrac blocks activation of the integrin response to tumor cell irradiation (974.6)

Abstract

We have described a thyroid hormone‐tetrac receptor on plasma membrane integrin αvβ3 that mediates hormone analogue regulation of cancer cell proliferation and of tumor‐related angiogenesis (PJ Davis et al., Annu Rev Pharmacol Toxicol 51:99‐115, 2011). Liganded to this receptor, tetrac and nanoparticulate tetract (Nanotetrac) radiosensitize cancer cells (AH Hercbergs et al., Cell Cycle 10[2]:352‐357, 2011). One mechanism of radiosensitization is impairment of cellular repair of DNA double‐stranded breaks. We have defined in human prostate cancer (PC‐3) cells grown on the chick chorioallantoic membrane (CAM) the response of αvβ3 to ionizing radiation in the absence and presence of tetrac and Nanotetrac. PC‐3 grafts grow spherically in the CAM system and develop a core of hypoxic cells. Lysates of untreated PC‐3 cells contain about 6,900 αvβ3 molecules/cell (DuoSet R&D Systems) and ionizing radiation with 1‐10 Gy increased the number of αvβ3 moles/cell approximately 5‐fold over this radiation dose range. Investigated for state of activation (open conformation) by flow cytometry, the integrin was indeed activated 7‐fold over the 1‐10 Gy radiation dose exposure range, a protective response. Treatment of cells with tetrac or Nanotetrac (1‐2.5 μg/CAM) prevented the increase in cell number of αvβ3 molecules in response to radiation and blocked radiation‐induced activation of the integrin. Thus, radiosensitization of tumor cells in the CAM model that is conferred by tetrac formulations is complex. Inhibition by tetrac and Nanotetrac of the activation of integrin αvβ3 leads, via intracellular signaling mechanisms, to disordered repair in the nucleus of double‐stranded DNA breaks.