Plk1 in chemoresistance of cancer Abstract: Paclitaxel and doxorubicin have been widely used to treat various cancers. However, one major problem for the failure of the chemotherapy is gradual development of resistance to drug-mediated cell death after prolonged exposure. Initially identified as a factor that leads to cell cycle arrest, p21CIP1/WAF1 can be induced by both p53-dependent and -independent mechanisms. As an inhibitor of cell proliferation, p21 plays an important role in drug-induced tumor suppression. However, it is now accepted that p21 can assume both pro- and anti- apoptotic functions after drug treatment depending on cellular context. For tumors with wild type p53, doxorubicin treatment causes activation of the p53/p21 pathway, resulting in cell cycle arrest and apoptosis. Inactivation of the p53/p21 pathway is required for subsequent recovery from doxorubicin-induced cell cycle arrest. In contrast, resistance to paclitaxel-mediated cell death has been correlated to elevated levels of p21 and knock-down of p21 restores paclitaxel sensitivity. Therefore, controlling p21 levels in tumor cells is critical for the efficacy of paclitaxel and doxorubicin, and possibly, other drugs. Because p21 is a short-lived and highly unstructured protein, modulation of its degradation rate significantly contributes to the regulation of its intracellular level. Association of p21 with the GTSE1/Hsp90/WISp39 complex in G2 phase and the Sgt1/Hsp90 complex in G1 phase protects it from degradation by the proteasome. In normal cells, p21 is degraded via the APCCdc20-dependent pathway in mitosis and the SCFSkp2-mediated pathway in S phase. However, p21 is stabilized in cancer cells throughout the cell cycle. Polo-like kinase 1 (Plk1), a critical regulator of many cell cycle-related events, is overexpressed in several types of cancers. Because we have identified GTSE1 and Sgt1 as two Plk1 substrates, we hypothesize that elevated levels of Plk1 in cancers promote p21 stability, thus contributing to chemoresistance. Our working model is as follows: Plk1 phosphorylation of GTSE1 prevents APCCdc20-mediated degradation of p21 in mitosis, and Plk1 phosphorylation of Sgt1 inhibits SCFSkp2-associated degradation of p21 in S phase. Both phosphorylation events lead to p21 stabilization, resulting in resistance of cancer cells to paclitaxel-mediated cell death. For cancer cells harboring WT p53, doxorubicin treatment results in cell cycle arrest. During the subsequent recovery, Plk1 phosphorylation of both Sgt1 and GTSE1 leads to inactivation of the p53 pathway to allow cell cycle re-entry, thus contributing to resistance of cancer cells to doxorubicin-mediated apoptosis. To test our hypothesis, we will first validate that Plk1 plays a critical role in resistance of cancer cells to paclitaxel/doxorubicin-mediated apoptosis. Mechanistically, we will determine how Plk1 phosphorylation of GTSE1 and Sgt1 regulates chemotherapy in both cultured cells and xenograft tumors. If successful, the predicted results will identify Plk1 as a novel target, inhibition of which will prevent chemoresistance, thus increasing the efficacy of chemotherapy.

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Plk1 in chemoresistance of cancer Narrative These studies will contribute to our understanding of the roles of Plk1 and its interacting proteins in resistance of cancer cells to two widely used chemotherapeutic agents: doxorubicin and paclitaxel. Since elevated Plk1 levels correlate with low survival rates of patients with several types of cancers, the long-term goal of our studies is to apply our knowledge and techniques to enhance the efficacy of chemotherapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Forry, Suzanne L
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Purdue University
Schools of Earth Sciences/Natur
West Lafayette
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Li, Zhiguo; Kong, Yifan; Song, Longzhen et al. (2018) Plk1-Mediated Phosphorylation of TSC1 Enhances the Efficacy of Rapamycin. Cancer Res 78:2864-2875
Zhang, Zhuangzhuang; Cheng, Lijun; Li, Jie et al. (2018) Inhibition of the Wnt/?-Catenin Pathway Overcomes Resistance to Enzalutamide in Castration-Resistant Prostate Cancer. Cancer Res 78:3147-3162
Shao, C; Chien, S-J; Farah, E et al. (2018) Plk1 phosphorylation of Numb leads to impaired DNA damage response. Oncogene 37:810-820
Mao, Fengyi; Li, Jie; Luo, Qian et al. (2018) Plk1 Inhibition Enhances the Efficacy of BET Epigenetic Reader Blockade in Castration-Resistant Prostate Cancer. Mol Cancer Ther 17:1554-1565
Kong, Yifan; Cheng, Lijun; Mao, Fengyi et al. (2018) Inhibition of cholesterol biosynthesis overcomes enzalutamide resistance in castration-resistant prostate cancer (CRPC). J Biol Chem 293:14328-14341
Wilking-Busch, Melissa J; Ndiaye, Mary A; Liu, Xiaoqi et al. (2018) RNA interference-mediated knockdown of SIRT1 and/or SIRT2 in melanoma: Identification of downstream targets by large-scale proteomics analysis. J Proteomics 170:99-109
Li, Jie; Wang, Ruixin; Kong, Yifan et al. (2017) Targeting Plk1 to Enhance Efficacy of Olaparib in Castration-Resistant Prostate Cancer. Mol Cancer Ther 16:469-479
Li, Zhiguo; Shao, Chen; Kong, Yifan et al. (2017) DNA Damage Response-Independent Role for MDC1 in Maintaining Genomic Stability. Mol Cell Biol 37:
Li, Zhiguo; Liu, Jinghui; Li, Jie et al. (2017) Polo-like kinase 1 (Plk1) overexpression enhances ionizing radiation-induced cancer formation in mice. J Biol Chem 292:17461-17472
Li, Zhiguo; Li, Jie; Kong, Yifan et al. (2017) Plk1 Phosphorylation of Mre11 Antagonizes the DNA Damage Response. Cancer Res 77:3169-3180

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