THE ROLE OF T-LAK CELL-ORIGINATED PROTEIN KINASE (TOPK) IN MODULATING PROSTATE CANCER STEMNESS AND ANDROGEN INDEPENDENCE

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Lama Mohammed Alhawas
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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 invasiveness potential. TOPK is a serine/threonine dual-specificity kinase characterized as a MAP kinase kinase due to its high homology to MKK3. Although TOPK is not detectable in most normal somatic adult tissue, including prostate tissue, its expression is high in prostate cancer and the majority of cancers and correlated to aggressive potential. However, the underlying molecular mechanism and functional consequences of TOPK overexpression in prostate cancer remain uncertain. My thesis aims to evaluate the role of TOPK in contributing to aggressive phenotypes of prostate cancer. We show here that genetic knockdown or pharmacological inhibition of TOPK down-regulates major stemness transcription factors in prostate cancer cells. Moreover, TOPK modulates prostate cancer stemness by governing c-MYC stability, an oncoprotein critical in prostate tumorigenesis and stemness. Furthermore, we identified a feed-forward reinforcement between TOPK and c-MYC, where TOPK regulates c-MYC stability, whereas c-MYC regulates TOPK expression. In addition, we also discovered that
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