Activation of tumor cell integrin αvβ3 by radiation and reversal of activation by chemically modified tetraiodothyroacetic acid (tetrac)

ABSTRACT

Purpose: Integrin αvβ3 is an important structural and signaling protein of the plasma membrane of cancer cells and dividing blood vessel cells. The plastic extracellular domain of the protein binds to extracellular matrix proteins and plasma membrane proteins, changing cell–cell interactions and generating intracellular signals that influence cell behavior. αvβ3 also contains a receptor for thyroid hormone and derivatives, including tetraiodothyroacetic acid (tetrac).

Materials and Methods: Human prostate cancer (PC3) cells were engrafted in the chicken chorioallantoic membrane model. The well-vascularized spheroidal xenografts were exposed to X-radiation in varying dosages (1–10 Gy) and in the presence and absence of an antibody that recognizes unliganded human β3 integrin monomer in the extended or open (activated) configuration.

Results: Radiation significantly increased activated β3 within 1 h (P < .001), a radiation response not previously reported. Incubation of cells with unmodified tetrac or tetrac covalently linked to a nanoparticle (Nanotetrac, NDAT) did not change basal activation state of the integrin monomer, but prevented radiation-induced activation of β3.

Conclusions: Activation of the integrin in response to radiation is interpreted as a defensive response, perhaps leading to increased intercellular affinity and inhibition of cell division, a radioresistant state. Action of NDAT indicates that pharmacologic interventions in the radiation response of integrin β3 monomer and therefore of αvβ3 are feasible.

KEYWORDS:

• Integrin
• integrin open configuration
• radioresistance
• tetrac
• thyroid hormone

Acknowledgments

This work was supported in part by a grant to JTL from NanoPharmaceuticals LLC, Rensselaer, NY.

Declaration of interest

Coauthors SAM and PJD own stock in NanoPharmaceuticals LLC, a pharmaceutical company that has developed Nanotetrac (NDAT). All other authors report no conflict of interest.

Additional information

Funding

This work was supported in part by a grant to JTL from NanoPharmaceuticals LLC, Rensselaer, NY.