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Simple Summary:
CDK9, in combination with Cyclin T1, is one of the major regulators of RNA Polymerase II mediated productive transcription of critical genes in any cell. The activity of CDK9 is significantly up-regulated in a wide variety of cancer entities, to aid in the overexpression of genes responsible for the regulation of functions, which are beneficial to the cancer cells, like proliferation, survival, cell cycle regulation, DNA damage repair and metastasis. Enhanced CDK9 activity, therefore, leads to poorer prognosis in many cancer types, offering the rationale to target it using small-molecule inhibitors. Several, increasingly specific inhibitors, have been developed, some of which are presently in clinical trials. Other approaches being tested involve combining inhibitors against CDK9 activity with those against CDK9’s upstream regulators like BRD4, SEC and HSP90; or downstream effectors like cMYC and MCL-1. The inhibition of CDK9’s activity holds the potential to be a highly effective anti-cancer therapeutic.
Abstract:
Cyclin Dependent Kinase 9 (CDK9) is one of the most important transcription regulatory members of the CDK family. In conjunction with its main cyclin partner—Cyclin T1, it forms the Positive Transcription Elongation Factor b (P-TEFb) whose primary function in eukaryotic cells is to mediate the positive transcription elongation of nascent mRNA strands, by phosphorylating the S2 residues of the YSPTSPS tandem repeats at the C-terminus domain (CTD) of RNA Polymerase II (RNAP II). To aid in this process, P-TEFb also simultaneously phosphorylates and inactivates a number of negative transcription regulators like 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) Sensitivity-Inducing Factor (DSIF) and Negative Elongation Factor (NELF). Significantly enhanced activity of CDK9 is observed in multiple cancer types, which is universally associated with significantly shortened Overall Survival (OS) of the patients. In these cancer types, CDK9 regulates a plethora of cellular functions including proliferation, survival, cell cycle regulation, DNA damage repair and metastasis. Due to the extremely critical role of CDK9 in cancer cells, inhibiting its functions has been the subject of intense research, resulting the development of multiple, increasingly specific small-molecule inhibitors, some of which are presently in clinical trials. The search for newer generation CDK9 inhibitors with higher specificity and lower potential toxicities and suitable combination therapies continues. In fact, the Phase I clinical trials of the latest, highly specific CDK9 inhibitor BAY1251152, against different solid tumors have shown good anti-tumor and on-target activities and pharmacokinetics, combined with manageable safety profile while the phase I and II clinical trials of another inhibitor AT-7519 have been undertaken or are undergoing. To enhance the effectiveness and target diversity and reduce potential drug-resistance, the future of CDK9 inhibition would likely involve combining CDK9 inhibitors with inhibitors like those against BRD4, SEC, MYC, MCL-1 and HSP90.
Since type and duration of an appropriate adjuvant chemotherapy in early-stage ovarian cancer (OC) are still being debated, novel markers for a better stratification of these patients are of utmost importance for the design of an improved chemotherapeutical strategy. In contrast to numerous cancer studies on cellular proliferation based on the immunohistochemistry-driven evaluation of protein expression, we compared mRNA and protein expression of two independent markers of cellular proliferation, Ki-67 and Plk1, in a large cohort of 243 early-stage OC and their relationship with clinicopathological features and survival. Based on marker expression we demonstrate that early-stage OC patients (stages I/II, low-grade, serous) with high expression (Ki-67, Plk1) had a significantly shorter progression-free survival (PFS) and overall survival (OS) compared to patients with low expression (Ki-67, Plk1). Remarkably, based on mRNA expression this significant difference got lost in advanced stages (III/IV): At least for PFS, high levels of Ki-67 and Plk1 correlate with moderately better survival compared to patients with low expressing tumors. Our data suggest that in addition to Ki-67, Plk1 is a novel marker for the stratification of early-stage OC patients to maximize therapeutic efforts. Both, Ki-67 and Plk1, seem to be better suited in early-stages (I/II) as therapeutical targets compared to advanced-stages (III/IV) OC.
Ligand stimulation of CD95 induces activation of Plk3 followed by phosphorylation of caspase-8
(2016)
Upon interaction of the CD95 receptor with its ligand, sequential association of the adaptor molecule FADD (MORT1), pro-forms of caspases-8/10, and the caspase-8/10 regulator c-FLIP leads to the formation of a death-inducing signaling complex. Here, we identify polo-like kinase (Plk) 3 as a new interaction partner of the death receptor CD95. The enzymatic activity of Plk3 increases following interaction of the CD95 receptor with its ligand. Knockout (KO) or knockdown of caspase-8, CD95 or FADD prevents activation of Plk3 upon CD95 stimulation, suggesting a requirement of a functional DISC for Plk3 activation. Furthermore, we identify caspase-8 as a new substrate for Plk3. Phosphorylation occurs on T273 and results in stimulation of caspase-8 proapoptotic function. Stimulation of CD95 in cells expressing a non-phosphorylatable caspase-8-T273A mutant in a rescue experiment or in Plk3-KO cells generated by CRISPR/Cas9 reduces the processing of caspase-8 prominently. Low T273 phosphorylation correlates significantly with low Plk3 expression in a cohort of 95 anal tumor patients. Our data suggest a novel mechanism of kinase activation within the Plk family and propose a new model for the stimulation of the extrinsic death pathway in tumors with high Plk3 expression.
Caspase-8 is an aspartate-specific cysteine protease, which is best known for its apoptotic functions. Caspase-8 is placed at central nodes of multiple signal pathways, regulating not only the cell cycle but also the invasive and metastatic cell behavior, the immune cell homeostasis and cytokine production, which are the two major components of the tumor microenvironment (TME). Ovarian cancer often has dysregulated caspase-8 expression, leading to imbalance between its apoptotic and non-apoptotic functions within the tumor and the surrounding milieu. The downregulation of caspase-8 in ovarian cancer seems to be linked to high aggressiveness with chronic inflammation, immunoediting, and immune resistance. Caspase-8 plays therefore an essential role not only in the primary tumor cells but also in the TME by regulating the immune response, B and T lymphocyte activation, and macrophage differentiation and polarization. The switch between M1 and M2 macrophages is possibly associated with changes in the caspase-8 expression. In this review, we are discussing the non-apoptotic functions of caspase-8, highlighting this protein as a modulator of the immune response and the cytokine composition in the TME. Considering the low survival rate among ovarian cancer patients, it is urgently necessary to develop new therapeutic strategies to optimize the response to the standard treatment. The TME is highly heterogenous and provides a variety of opportunities for new drug targets. Given the variety of roles of caspase-8 in the TME, we should focus on this protein in the development of new therapeutic strategies against the TME of ovarian cancer.