Pharmacology and Toxicology

Sanjay Kansra, PhD Assistant Professor PhD, University of Missouri, Pharmacology (1995) Endocrine Pharmacology Telephone: 414-456-7376 E-mail: skansra@mcw.edu

Hyperprolactinemia, over production of prolactin (PRL), is a major cause of infertility in women and impotence in men, and thus understanding regulation of PRL production and release is of vital interest. The pituitary lactotrophs express a and b types of estrogen receptors (ER) and respond to estrogens by increased PRL release and proliferation. Although the role of estrogens in regulating lactotroph function is well established, the ER subtype contribution in these processes is unknown. Using rat pituitary lactotrophs, GH3 cells, we found that 17b estradiol, (E2), PPT (ERa specific agonist), DPN (ERb specific agonist) and xenoestrogen, bisphenol A (BPA) induced PRL release, whereas only E2 and PPT stimulated cell proliferation. Further, all ligands activated Erk-1,2, suggestive of a common initial signaling mechanism. We are now characterizing the ER subtypes and their signaling mechanisms that mediate E2 and xenoestrogen responses in lactotrophs.

We have also found that in absence of E2, the "pure" anti-estrogen ICI 182,780 (ICI) rapidly degrades ERa via the proteosome and suppresses both PRL production/release and cell proliferation. Notably, E2, which stimulates cell proliferation and PRL release/gene expression, also causes rapid proteosomal degradation of ERa. This suggests that ERa, occupied by E2 or ICI, is proteolytically processed in distinct manners. We are identifying early events that occur upon ER occupation by agonists and antagonists, which might explain the different biological responses to these compounds.

It is now well accepted that there exists a bidirectional "cross-talk" between ER and growth factor receptors. These interactions have been extensively characterized in the breast and uterus, but this status is unknown in lactotrophs. We show that epidermal growth factor (EGF) is a weak mitogen in lactotrophs, but in the presence of sub-nanomolar amounts of E2, a potent Erk-1,2-dependent synergism in stimulation of lactotroph proliferation is observed. We are currently investigating the status of ER:EGFR interactions in the lactotrophs, both in the presence and absence of E2.

Recent Publications

Stoll, S, Kansra, S, and Elder, J.T. Metalloproteinases stimulate ErbB dependent ERK signaling in human skin organ culture. J. Biol. Chem, 297(30): 26839-45, 2002.

Kansra, S, Stoll, S.W, and Elder, J,T. Preferential cytoskeletal association of ErbB1R compared to ErbB2R in normal human keratinocytes. BBRC, 295(5): 1108-17, 2002.

Kansra, S, Stoll, S.W., Johnson, J. and Elder, J.T. Autocrine ERK activation in normal human keratinocytes: metalloproteinase-mediated release of amphiregulin triggers signaling from ErbB1 to ERK. Mol. Biol. Cell. 15(9): 4299-309. 2004.

Kansra, S, Stoll, S.W., Johnson, J. and Elder, J.T. Src Family kinase inhibitors block amphiregulin mediated autocrine ErbB signaling in normal human keratinocytes Mol. Pharm. 67(4): 1145-57, 2005.

Kansra, S., Yamagata, S., Sneade, L, Foster, L, and Ben-Jonathan, N. Differential effects of estrogen receptor antagonists on pituitary lactotroph proliferation and prolactin release. Mol. Cell. Endocrinology, 239(1-2): 27-36, 2005.

Rittié L, Kansra S, Stoll SW, Li Y, Gudjonsson JE, Shao Y, Michael LE, Fisher GJ, Johnson TM, Elder JT. Differential ErbB1 signaling in squamous cell versus basal cell carcinoma of the skin. Am J Pathol. 2007 Jun;170(6):2089-99.

Ben-Jonathan N, Chen S, Dunckley JA, Lapensee C, Kansra S. Estrogen Receptor {alpha} Mediates the Epidermal Growth Factor-Stimulated Prolactin Expression and Release in Lactotrophs. Endocrinology.  2009 Feb;150(2):795-802.

Miller M, Chen S, Woodliff J, Kansra S. Curcumin (diferuloylmethane) inhibits cell proliferation, induces apoptosis and decreases hormone levels and secretion, in pituitary tumor cells.  Endocrinology. 2008 Aug;149(8):4158-67.

Chen S., Bangaru M.L.Y., Sneade L., Dunckley J.A., Ben-Jonathan N. and Kansra S. Epidermal Growth Factor Receptor cross-talks with ligand occupied Estrogen Receptor-alpha to modulate both lactotroph proliferation and prolactin gene expression. American Journal of Physiology Endocrinology & Metabolism, Aug;297(2):E331-9. 2009.

Bangaru M.L.Y., Woodliff J, Raff H., and Kansra S.H Growth suppression of mouse pituitary corticotroph tumor AtT20 cells by curcumin: a model for treating Cushing's disease. PLoS One, Apr 13;5(4):e9893, 2010.

Kansra S, Chen S, Bangaru MLY, Sneade L, Dunckley JA, and Ben-Jonathan N. Selective estrogen receptor down-regulator and selective estrogen receptor modulators differentially regulate lactotroph proliferation.  PLoS One, Apr 19;5(4):e10060, 2010.

Bangaru M.L.Y., Chen S, Woodliff J and Kansra S.HH Curcumin (diferuloylmethane) induces apoptosis and blocks migration of human medulloblastoma cells. Anticancer Research,  Feb;30(2):499-504, 2010.