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The Role of AKT1 And IKKβ in Ovarian Cancer Tumorigenesis and Chemotherapeutic Resistance

Niculaita, Roxana
http://rave.ohiolink.edu/etdc/view?acc_num=kent1227665461

Abstract Details

2008, PHD, Kent State University, College of Arts and Sciences / School of Biomedical Sciences.
Ovarian cancer is the seventh most common cancer in women and the fourth most frequent cause of cancer death in US. Ovarian cancer has the highest mortality of all cancers of the female reproductive system, reflecting, in part, a lack of early symptoms and proven ovarian cancer screening tests. NFκB and β-catenin are two transcription factors important in regulating the expression of genes that control cell proliferation, cell survival and transformation. Our laboratory has found that the phosphatidylinositol 3’ kinase (PI3K)/AKT/ IκB kinase (IKK) pathway aberrantly activates both NFκB and β-catenin in cancer. Our hypothesis is that aberrant activation of AKT and IKKs may cause the deregulation and inappropriate activation of both the NFκB and β-catenin signal transduction pathways, which may lead to the development of ovarian cancer by promoting cellular transformation, uncontrolled cell division and resistance to apoptosis. We used RNAi technology to specifically knockdown the expression of AKT1 and IKKβ and determined the effects of the loss of either AKT1 or IKKβ on the regulation of the NFκB and β-catenin signal transduction pathways as well as on the tumorigenic characteristics and chemotherapeutic resistance of SKOV-3 and A2780 ovarian cancer cell lines. Loss of either IKKβ or AKT1 significantly inhibited both the inappropriate basal and TNFα-induced NFκB transcriptional activity and loss of IKKβ reduced TNFα-induced NFκB DNA binding in the SKOV-3 and A2780 ovarian cancer cell lines. Also, IKKβ knockdown significantly inhibited both the basal and Wnt-stimulated β-catenin-dependent transcriptional activity in A2780 ovarian cancer cell line. The loss of AKT1 but not IKKβ inhibited anchorage independent growth in both the SKOV-3 and A2780 ovarian cancer cells. Knockdown of either AKT1 or IKKβ inhibited both the migration and invasion of the A2780 ovarian cancer cells, while causing only an inhibition of the invasive capacity in SKOV-3 ovarian cancer cells, without affecting migration of these cells. Loss of either AKT1 or IKKβ in A2780 ovarian cancer cells increased chemotherapeutic sensitivity to paclitaxel, while interestingly these knockdowns in SKOV3 ovarian cancer cells increased chemotherapeutic sensitivity to cisplatinum. Our results suggest that AKT1 and IKKβ are two major molecules involved in ovarian cancer progression. Finding new targeting approaches for these molecules and their downstream effectors could provide a successful approach for screening and treating patients with ovarian cancer.
Nywana Sizemore, PhD (Advisor)
Brent Bruot, PhD (Committee Member)
Jennifer Marcinkiewicz, PhD (Committee Member)
Gail Fraizer, PhD (Committee Member)
John R.D. Stalvey, PhD (Committee Member)
145 p.
Biomedical Research
ovarian cancer, AKT1, IKK&946; , NF&954; B, &946; -catenin, invasion, migration, Cisplatin, Paclitaxel

Recommended Citations

Citations

  • Niculaita, R. (2008). The Role of AKT1 And IKKβ in Ovarian Cancer Tumorigenesis and Chemotherapeutic Resistance [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1227665461

    APA Style (7th edition)

  • Niculaita, Roxana. The Role of AKT1 And IKKβ in Ovarian Cancer Tumorigenesis and Chemotherapeutic Resistance. 2008. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1227665461.

    MLA Style (8th edition)

  • Niculaita, Roxana. "The Role of AKT1 And IKKβ in Ovarian Cancer Tumorigenesis and Chemotherapeutic Resistance." Doctoral dissertation, Kent State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=kent1227665461

    Chicago Manual of Style (17th edition)

kent1227665461
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© 2008, all rights reserved.
This open access ETD is published by Kent State University and OhioLINK.