Xiao-Kun Zhang's Research Focus
Dr. Xiao-kun Zhang studies the chemopreventive and therapeutic effects of Vitamin A and its synthetic analogs in various cancers and other diseases. He discovered a new vitamin A signaling pathway through RXR protein complexes. An agent that modulates RXR activities has been approved by the FDA for treating lymphoma patients and is now in phase III clinical trial for lung cancer. Dr. Zhang also found that a gene that binds Vitamin A (called RARb) acts as a tumor suppressor. His group studies how RARb prevents tumor development. They recently discovered a new paradigm for destroying cancer cells using a protein called TR3, or Nur77. TR3 is often present at high levels in cancer cells to promote their growth in the nucleus. Dr. Zhang recently showed that he is able to move TR3 from the nucleus to the mitochondria. In mitochondria, TR3 binds to Bcl-2, a protein that maintains tumor growth. The binding converts Bcl-2 from a tumor protector to a tumor destroyer. Dr. Zhang's laboratory is now exploring the possibility of treating cancer patients using a class of specific agents that induce TR3 migration
Xiao-Kun Zhang's Research Report
Retinoids and Their Receptors in Cancer
Our laboratory focuses on the retinoid receptors in cancer cells and the development of new retinoids with optimal anti-cancer activities. Retinoids are a group of natural and synthetic vitamin A analogs and are promising agents for the prevention and treatment of a variety of cancers and diseases. The major limitation to the application of retinoids is the retinoid resistance observed in cancer cells. Our goal is to understand how anticancer activities of retinoids are regulated and how cancer cells acquire resistance to retinoids with the aim of restoring retinoid sensitivity in cancer cells and developing more effective retinoids for cancer prevention and treatment.
The anti-cancer effects of retinoids are mainly mediated by their nuclear receptors, the retinoic acid (RA) receptors (RARs) and the retinoid X receptors (RXRs). During the last few years, we have devoted our effort to understand the mechanisms by which retinoids inhibit cancer cell growth. We found that retinoids can promote apoptosis in breast cancer and lung cancer cells and that induction of apoptosis and growth inhibition by retinoids is largely mediated by RARbeta. Our results suggest that RARbeta may function as a tumor suppressor gene in lung and breast carcinogenesis, and that loss of RARbeta may contribute to the tumorigenicity and retinoid resistance of cancer cells.
New Retinoid Signaling in Cancer Cells
We showed that the conventional retinoids, such as trans-RA, effectively induce RARbeta expression and inhibit the growth of hormone-dependent but not hormone-independent breast cancer cells. Induction of RARbeta in hormone-dependent breast cancer cells is mediated by RAR/RXR heterodimer that binds to the RA response element (beta RARE) in the RARbeta promoter. Recently, we have identified a new pathway to induce RARbeta in hormone-independent breast cancer cells by using RXR-selective retinoids, such as 9-cis RA. This pathway is mediated by RXR/nur77 heterodimer that binds to the same beta RARE. Thus, depending on levels of RAR, RXR and nur77, either a RAR or a RXR signaling pathway can induce RARbeta expression and apoptosis in breast cancer cells (Figure 1). Such a retinoid signaling switch may play an important role in regulating cell growth in response to different stimuli, and it suggests that different retinoids can be used to inhibit the growth of different types of breast cancer.
New Apoptosis-inducing Retinoids
6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN or CD437) was originally identified as a retinoic acid receptor g (RARg)-selective retinoid. We investigated the role of AHPN/CD437 and its mechanism of action in human lung cancer cell lines. Our results demonstrated that AHPN/CD437 effectively inhibited lung cancer cell growth by inducing G0/G1 arrest and apoptosis, a process that is accompanied by rapid induction of cJun, nur77 and p21. In addition, we found that expression of p53 and Bcl-2 was differentially regulated by AHPN/CD437 in different lung cancer cell lines and may play a role in regulating AHPN/CD437-induced apoptotic process. Furthermore, overexpression of nur77 anti-sense RNA in A549 and H460 lung cancer cell lines largely inhibited AHPN/CD437-induced apoptosis. Thus, expression of nur77 plays a critical role in AHPN/CD437-induced apoptosis. Together, our study reveals a novel pathway for retinoid-induced apoptosis and suggests that AHPN/CD437 or analogs may have a better therapeutic efficacy against lung cancer.
Regulation of RARbeta Expression and Retinoid Sensitivity by Orphan Receptor COUP-TF
How RARbeta expression is regulated and how its expression is lost in cancer cells remain largely unknown and are subject to intensive studying. Expression of RARbeta is highly induced by RA and and requires RAR and RXR that bind to the beta RARE present in its promoter. However, expression of RARs and RXRs is not sufficient to render RARbeta expression responsive to RA. In searching for factors, other than RARs and RXRs, that are required for RARbeta expression and responsible for loss of retinoid sensitivity in cancer cells, we have identified that orphan receptor COUP-TF plays a key role in modulating RARbeta expression and retinoid sensitivity in cancer cells. Expression of COUP-TF is positively correlated with RARbeta induction and growth inhibition by RA in various cancer cell lines. Our stable transfection assays showed that expression of COUP-TF in COUP-TF-negative cancer cells enhanced induction of RARbeta expression, growth inhibition and apoptosis by RA, while inhibition of COUP-TF by expression of COUP-TF anti-sense RNA in COUP-TF-positive cells repressed the ability of RA to induce RARbeta expression, growth inhibition and apoptosis in the cells. In transient transfection assay, COUP-TF strongly induced transcriptional activity of the RARbeta promoter in a RA- and RARalpha -dependent manner. The effect of COUP-TF requires both a DR-8 element that binds strongly with COUP-TF and the beta RARE in the RARbeta promoter. Mutations that either abolished COUP-TF binding to the DR-8 element or RARalpha binding to the beta RARE impaired RA- and RARalpha - dependent transactivation function of COUP-TF. By GST-pull-down assay, we observed that COUP-TF, through its interaction with RARalpha alpha with its co-activator CBP, suggesting that COUP-TF functions as an accessory protein for RARalpha to induce RARbeta promoter transcription. Together, our results demonstrate that COUP-TF is required for RA-dependent RARbeta induction, growth inhibition and apoptosis by acting as an accessory protein for RARalpha to recruit its co-activator (Figure 2). The facts that COUP-TF is not expressed in many cancer cell lines and that loss of RARbeta is an early event in carcinogenesis suggest that COUP-TF may have a role in cancer development.
Retinoid signaling pathways in breast cancer cells. RARbeta expression can mediate the growth inhibitory effect of retinoids and is regulated by the beta RARE in the RARbeta promoter. The beta RARE binds both RXR/RAR and RXR/nur77 heterodimers. Relative levels of RAR, RXR and nur77 may determine whether beta RARE binds to a particular heterodimer. Hormone-dependent breast cancer cells express high level of RARalpha to favor binding of RXR/RAR heterodimer that is activated by RAR-selective retinoids to induce RARbeta alpha to favor RXR/nur77 heterodimer, which binds to the beta RARE and induce RARbeta expression in response to RXR-selective retinoids.
Regulation of RARbeta promoter activity by COUP-TF. COUP-TF, upon binding to its response element (COUP-TF-RE), interacts with RARbeta that binds to the beta RARE as RAR/RXR heterodimer. The interaction leads to a conformational change of RAR/RXR heterodimer, that could effectively interact with retinoid receptor co-activator CBP, resulting in increase of RARbeta promoter activity and RARbeta.
Xiao-Kun Zhang's Bio
Xiao-kun Zhang earned his Ph.D. in biochemistry from the University of Vermont in 1989. Dr. Zhang spent three years as a postdoctoral fellow at SBP prior to his appointment to the faculty in 1992.
Ph.D., University of Vermont, Biochemistry, 1989