Ovarian cancer is the most lethal gynecological malignancy. Most of ovarian
cancer patients relapse and subsequently die due to the development of resistance
to chemotherapy. P73 belongs to the tumor suppressor p53 family. Like p53, the
transcriptionally active TAp73 can bind specifically to p53 responsive elements
and transactivates some of the p53 target genes, and finally leads to cell cycle
arrest and apoptosis. TAp73 can be induced by DNA damage to enhance cellular
sensitivity to anticancer agents in human cancer cells. However, the functions of
TAp73 in ovarian cancer cells and the role in the regulation of cellular response to
commonly used chemotherapeutic agents cisplatin are still poorly understood. The
aims of this study were to examine the functions of TAp73 in ovarian cancer cells
and its role in cellular response to cisplatin, as well as the relationship between
TAp73 and p53 in ovarian cancer cells.
Functional studies showed that over-expression of TAp73alpha (TAp73α)
inhibited cell proliferation, colony formation ability and anchorage-independent
growth of ovarian cancer cells, and this was irrespective of p53 expression status.
In addition, TAp73α inhibited cell growth by arresting cell cycle at G2/M phase
and up-regulating the expressions of G2/M regulators of p21, 14-3-3sigma and
GADD45α.
TAp73α enhanced the cellular sensitivity to cisplatin through the activation of
JNK signaling pathway, at least partially, in ovarian cancer cells. TAp73α
activated the JNK pathway through the up-regulation of its target gene GADD45α
and subsequent activation of MKK4, the JNK up-stream kinase. Inhibition of JNK
activity by a specific inhibitor (SP600125) or small interfering RNAs (siRNAs)
significantly abrogated TAp73-mediated apoptosis induced by cisplatin. Moreover,
the activations of MKK4, JNK and c-Jun were abolished when GADD45α was
knocked down by siRNAs, and the JNK-dependent apoptosis was not observed.
Collectively, these results supported that TAp73α was able to mediate apoptotic
response to cisplatin through the GADD45α/MKK4/JNK signaling pathway,
which was respective of p53 expression status.
Further investigation on the relationship between TAp73α and p53
demonstrated that TAp73α increased p53 protein, but not mRNA expression by
attenuating p53 protein degradation in wild-type p53 ovarian cancer cells.
TAp73α could directly interact with p53 protein, which might interfere with the
binding ability of MDM2 to p53, and consequently block the p53 protein
degradation. In addition, TAp73α inactivated the Akt and ERK pathways and
activated the p38 pathway in response to cisplatin in wild-type p53 OVCA433,
but not in null-p53 SKOV3 cells, suggesting that the effect of TAp73α on these
pathways might be p53-dependent. These results indicated that a functional
cooperation of TAp73α and p53, to some extent, existed in ovarian cancer cells.
In conclusion, this study demonstrated that TAp73α acted as a tumor
suppressor in ovarian carcinogenesis. It promoted the cellular sensitivity to
cisplatin via, at least partially, the activation of JNK signaling pathway. These
TAp73α functions were irrespective of p53 expression. In addition, TAp73α was
able to bind to p53 and increase p53 expression. / published_or_final_version / Obstetrics and Gynaecology / Doctoral / Doctor of Philosophy
| Identifer | oai:union.ndltd.org:HKU/oai:hub.hku.hk:10722/174474 |
| Date | January 2011 |
| Creators | Zhang, Pingde., 张萍德. |
| Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
| Source Sets | Hong Kong University Theses |
| Language | English |
| Detected Language | English |
| Type | PG_Thesis |
| Source | http://hub.hku.hk/bib/B47752944 |
| Rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works., Creative Commons: Attribution 3.0 Hong Kong License |
| Relation | HKU Theses Online (HKUTO) |
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