Loss of Gprc5A Enhances Survival In Normal and Malignant Lung Epithelial Cells By Eliciting Persistent Stat3 Activation Induced By Autocrine Lif

<p>Signal transduction and activator of transcription 3 (Stat3) is activated by cytokines and growth factors in many cancers. Persistent activation of Stat3 plays important role in cell growth, survival, and transformation through regulating its targeted genes. </p> <p>Previously, we found that mice with a deletion of the G protein-coupled receptor, family C, group 5, member a (Gprc5a) gene develop lung tumors indicating that Gprc5a is a tumor suppressor. In the present study, we examined he mechanism of Gprc5a-mediated tumor suppression. We found that epithelial cells from <em>Gprc5a</em> knockout mouse lung (<em>Gprc5a</em>^-/- cells) survive better in vitro in medium deprived of exogenous growth factors and form more colonies in semi-solid medium than their counterparts from wildtype mice (<em>Gprc5a</em>^+/+ cells). The phosphorylation of tyrosine 705 on Stat3 and the expression of Stat3-regulated anti-apoptotic genes Bcl-XL, Cryab, Hapa1a, and Mcl1 were higher in the <em>Gprc5a</em>^-/- than in <em>Gprc5a</em>^+/+ cells. In addition, their responses to Lif were different; Stat3 activation was persistent by Lif treatment in the <em>Gprc5a</em>^-/- cells, but was transient in the <em>Gprc5a</em>^+/+ cells. The persistent activation of Stat3 by Lif in <em>Gprc5a</em>^-/- cells is due to a decreased level of Socs3 protein, a negative inhibitor of the Lif-Stat3 signaling. Restoration of Socs3 inhibited the persistent Stat3 activation in <em>Gprc5a</em>^-/- cells. Lung adenocarcinoma cells isolated from <em>Gprc5a</em>^-/- mice also exhibited autocrine Lif-mediated Stat3 activation. Treatment of <em>Gprc5a</em>^-/- cells isolated from normal and tumor tissue with AG490, a Stat3 signaling inhibitor, or with dominant negative Stat3(Y705F) increased starvation-induced apoptosis and inhibited anchorage-independent growth. </p> <p>These results suggest that persistent Stat3 activation increased the survival and transformation of <em>Gprc5a</em>^-/- lung cells. Thus, the tumor suppressive effects of Gprc5a are mediated, at least in part, by inhibition of Stat3 signaling through regulating the stability of the Socs3 protein.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2010

Author dc:creator

• Chen, Yulong

Contributors dc:contributor

• Reuben Lotan, Ph.D.
• Pierre D. McCrea, Ph.D.
• Faye M Johnson, MD, Ph.D.

• lung cancer
• Gprc5a
• tumor suppressor
• Stat3
• Lif
• survival
• Cancer Biology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/61

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1086