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XIAO-KUN ZHANG, PH.D.
Professor
Tumor Development
858.646.3141 (phone)
858.646.3195 (fax)
xzhang@burnham.org
RESEARCH FOCUS, BIOGRAPHY, PUBLICATIONS
Research Focus
Dr. Xiao-kun Zhang studies the chemopreventive and therapeutic effect of Vitamin A and its synthetic analogs in various cancers and diseases. Dr. Zhang 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 now in phase III clinical trial for lung cancer. Dr. Zhang found that a gene called RARb that binds Vitamin A acts as a tumor suppressor and is studying how RARb prevents tumor development. Recently, Dr. Zhang discovered a new paradigm for destroying cancer cells by using a protein called TR3 or Nur77. TR3 is often present at high levels in cancer cells to promote their growth in an intracellular compartment called nucleus. Dr. Zhang recently showed that he is able to move TR3 from the nucleus to another intracellular organelle called mitochondria. In mitochondria, TR3 binds to Bcl-2, a protein that maintains the growth of tumor. The binding converts Bcl-2 from a tumor protector to a tumor destroyer. Dr. Zhang is now exploring the possibility of using a class of specific agents that induce TR3 migration for treating cancer patients.
Biography
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 the Burnham Institute for Medical Research prior to his appointment to the faculty in 1992.
Selected Publications
Li, H., Kolluri, S.,
Gu, J., Dawson, M.I., Cao, X., Hobbs, P. Lin, B., Chen, G.-q., Lu,
J.-s., Lin, F., Fontana, J. A., Reed, J. C., and Zhang, X.-k.
Mitochondrial Targeting of Orphan Receptor TR3/nur77 Induces Cytochrome
C Release and Apoptotic Cell Death. Science. 289: 1159-1164, 2000.
Lin,
F., Kolluri, S., Chen, G.-q.and Zhang, X.-k. Regulation of Retinoic
Acid-induced Inhibition of AP-1 Activity by Orphan Receptor COUP-TF. J.
Biol. Chem. 277: 21414-22, 2002.
Zhang, X.-k. Vitamin A and apoptosis in prostate cancer. Endocrine-Related Cancer. 9: 87-102, 2002.
Dawson
MI, Zhang X-k. Discovery and design of retinoic acid receptor and
retinoid X receptor class- and subtype-selective synthetic analogs
ofall-trans-retinoic acid and 9-cis-retinoic acid. Curr. Med. Chem. 9:
623-37. 2002.
Kolluri, S., Cao, X., Bruey-Sedano, N., Lin, B.,
Lin, F., Han, Y.-H., Dawson, M.I., and Zhang, X.k. Mitogenic Effect of
Orphan Receptor TR3 and its Regulation by MEKK1 in Lung Cancer Cells.
Mol. Cell. Biol. 23: 8651-8667 2003.
James, S., Lin, F.,
Kolluri, S., Dawson, M.I., and Zhang, X.-k. Regulation of retinoic acid
receptor b expression by peroxisome proliferator-activated receptor g
ligands in cancer cells. Cancer Res. 63: 3531-3538. 2003.
Lin,
B., Kolluri, S., Cao, X., Li, H., Han, Y.-h., Lin, F., Reed, J.C., and
Zhang, X.-k. Conversion of Bcl-2 from Protector to Killer by
Interaction with Nuclear Orphan Receptor Nur77/TR3. Cell. 116: 527-540.
2004.
List of Publications via PubMed
(NIH National Library of Medicine)
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
