2006 — 2007 |
Kadakia, Madhavi P |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Elucidate the Role of P63 in Prostate Cancer Progression @ Wright State University
[unreadable] DESCRIPTION (provided by applicant): Prostate cancer is one of the frequently detected cancers in males and the second leading cause of death in males. Vitamin D analogues are widely used for prostate cancer chemotherapy and exerts its anti-proliferative activities through the Vitamin D receptor (VDR) signaling pathway. The p63 gene, a member of the p53 tumor suppressor gene family, plays a critical role in prostate development. Mice lacking p63 exhibit not only severe developmental defects but lack a prostate organ as well. Recently, epithelial stem cells have been implicated in prostate growth and disease. p63 is expressed in the basal cells of the prostate and abnormal p63 expression has been associated with neoplastic transformation of the prostate. The complex structure of p63 gives rise to six different isoforms that either act as transcriptional activators or repressors. The balance between the levels of different p63 isoforms plays an important role in deciding the fate of cell proliferation/differentiation. Preliminary data in our laboratory demonstrated that TAp63 expression leads to the induction of several genes involved in the VDR pathway. This research proposal is aimed at dissecting the role of p63 in the VDR signaling pathway and subsequently its role in prostate cancer progression. Our hypothesis is that p63 isoforms exert differential effects on cell growth and survival through regulation of the VDR pathway. The research effort proposed here may not only reveal important information about the role of p63 and VDR signaling in understanding the development of prostate cancer but assist in the development of therapeutic strategies in the treatment of prostate cancer. [unreadable] [unreadable] [unreadable]
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0.958 |
2012 — 2016 |
Kadakia, Madhavi P |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Deltanp63alpha in Vitamin D Mediated Cell Survival in Skin Cancer @ Wright State University
DESCRIPTION (provided by applicant): Skin cancer is the most common cancer in United States. The rise in the incidence of non-melanoma skin cancers (NMSCs), namely Basal cell carcinoma (BCC) and Squamous cell carcinoma (SCC), and growing cost of treatment warrants research into the basic etiologies of these cancers in order to design better treatment regimens. Although UV exposure is the leading cause of skin cancer, it is also required for the cutaneous production of 1¿, 25 dihydroxyvitamin D (vitamin D, VD3). Use of vitamin D as a chemotherapeutic adjuvant has been explored since it promotes cellular differentiation, decreases cancer cell growth, and induces apoptosis. Contrary to those beneficial attributes, vitamin D has recently been shown to promote cell survival by activating the well-known PI3K/Akt cell survival pathway and inhibiting the JNK pathway, which induces apoptosis. VD3 exerts its effects upon binding to the vitamin D receptor, VDR. We have previously shown that VDR is positively regulated by the most abundant and physiologically relevant p63 isoform, ¿Np63a. Both ¿Np63a and VDR are present in the basal layer of the epidermis and are critical to the maintenance of a stratified epidermis. Our preliminary data indicate that VDR/VD3 in turn also positively regulates ¿Np63a, creating a positive feedback loop. We will test the hypothesize that VDR/VD3 directly enhances the expression of DNp63a and indirectly stabilizes DNp63a via Akt activation or JNK inhibition thereby leading to increased cell survival and tumor cell progression. The specific aims of this proposal are: (1) Delineate the mechanisms by which VD3 leads to enhanced ¿Np63a levels. In this aim we will test the hypothesis that DNp63a is directly regulated by VDR/VD3 and indirectly via VD3 mediated regulation of Akt activation or JNK inhibition. (2) Determine whether ¿Np63a mediates VD3 induced pro-survival activity. In this aim will test the hypothesis that increased cell survival observed upon VD3 treatment, occurring via either Akt activation or inhibition of JNK requires DNp63a. (3) Determine the role of the VDR- ¿Np63a signaling pathways in skin cancer development using mouse models and primary human skin tumor tissues. In this aim we will test the hypothesis that VDR/Akt/JNK/¿Np63a signaling pathways impact skin cancer development by evaluating the expression and correlation between each of the components of this pathway in tumor tissues from patients with SCC, BCC and actinic keratosis. The involvement of VD3, VDR and ¿Np63a in UV induced skin cancer development will also be tested in VDR null mice and SKH-1 mice, a model for SCC. The proposed studies will address major knowledge gaps regarding the biology of ¿Np63a and VDR in skin cancer, which in turn will lead to better understanding of tumor development and towards more effective use of VD3 as a cancer treatment. PUBLIC HEALTH RELEVANCE: Vitamin D mediates regulation of two independent pathways involved in promoting cell survival or apoptosis with the assistance of ¿Np63¿ and VDR. Understanding the mechanism by which these pathways are regulated by vitamin D will not only improve use of Vitamin D in cancer therapy but provide clues to the development and progression of skin cancer.
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0.958 |