Dissertation Defense: Lama Alhawas
Candidate Name: Lama Alhawas
Major: Biochemistry and Molecular & Cellular Biology
Advisor: Partha P. Banerjee, Ph.D.
Title: The Role of T-Lak Cell-Originated Protein Kinase (TOPK) in Modulating Prostate Cancer Stemness and Androgen Independence
The predominant clinical challenge in the treatment of prostate cancer (CaP) is how to differentiate aggressive CaP from indolent ones. Previously, our lab has demonstrated that a protein kinase, T-LAK cell-originated protein kinase (TOPK) levels are high in tumorigenic tissue compared with normal and benign prostatic hyperplasia and correlated with higher grades of prostate cancer and its invasive potential. TOPK is a serine/threonine dual-specificity kinase characterized as a MAP kinase kinase due to its high homology to MKK2,3. Although TOPK is not detectable in most normal somatic adult tissue, including prostate tissue, its expression is high in prostate cancer and correlated to aggressive potential. My thesis aims to evaluate the role of TOPK in contributing to aggressive phenotypes of prostate cancer. We show here that TOPK regulates major stemness transcription factors in prostate cancer cells and modulates prostate cancer stemness by governing c-MYC stability. Furthermore, we identified a feed-forward reinforcement between TOPK and c-MYC. Overexpression of TOPK in androgen-dependent VCaP and LNCaP prostate cancer cells enhances the alternatively spliced variant ARv7 protein levels and drives androgen-independence. As a result, pharmacological inhibition of TOPK by OTS-514 represses transcriptional activation of the androgen receptor and AR stability. The work presented in this thesis unravels novel roles of TOPK in mediating aggressiveness in prostate cancer by enhancing the stability of c-MYC, AR, and ARv7 and thereby maintaining stemness and androgen-independence. Therefore, our overall work proposes that TOPK may serve as an attractive target in the treatment of aggressive prostate cancer.