PDK1 Signaling Toward PLK1–MYC Activation Confers Oncogenic Transformation, Tumor-Initiating Cell Activation, and Resistance to mTOR-Targeted Therapy

Abstract

Although 3-phosphoinositide-dependent protein kinase-1 (PDK1) has been predominately linked to the phosphoinositide 3-kinase (PI3K)-AKT pathway, it may also evoke additional signaling outputs to promote tumorigenesis. Here, we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces MYC phosphorylation and protein accumulation. We show that PDK1-PLK1-MYC signaling is critical for cancer cell growth and survival, and small-molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting of MYC dependency. Intriguingly, PDK1-PLK1-MYC signaling induces an embryonic stem cell-like gene signature associated with aggressive tumor behaviors and is a robust signaling axis driving cancer stem cell (CSC) self-renewal. Finally, we show that a PLK1 inhibitor synergizes with an mTOR inhibitor to induce synergistic antitumor effects in colorectal cancer by antagonizing compensatory MYC induction. These fi ndings identify a novel pathway in human cancer and CSC activation and provide a therapeutic strategy for targeting MYC-associated tumorigenesis and therapeutic resistance. SIGNIFICANCE:This work identifi es PDK1-PLK1-MYC signaling as a new oncogenic pathway driving oncogenic transformation and CSC self-renewal. Targeted inhibition of PDK1/PLK1 is robust in targeting MYC dependency in cancer cells. Thus, our fi ndings provide important insights into cancer and CSC biology and have signifi cant therapeutic implications. Cancer Discov; 3(10); 1156-71.

PLK1 Phosphorylates PAX3-FOXO1, the Inhibition of Which Triggers Regression of Alveolar Rhabdomyosarcoma

“…It has previously also been shown that PAX3-FOXO1 has increased posttranslational stability compared with wild-type proteins (21). Our results are furthermore in line with studies demonstrating PLK1 to mediate stabilization of transcription factors such as the oncogene MYC (49). Interestingly, we found the fusion target gene NMYC to be degraded upon PLK1 inhibition, either by a direct or indirect mechanism ( Supplementary Fig.…”

Phosphoinositide Protein Kinase PDPK1 Is a Crucial Cell Signaling Mediator in Multiple Myeloma

“…Furthermore, our data also revealed that PDPK1 regulates the MYC/IRF4 axis, which is essential for myeloma cell survival (44). Presumably, PDPK1 regulates the expression of c-MYC and IRF4 in myeloma cells, at least in part via PLK1, RSK2, and AKT (25,36,43,44). CCNDs, which are critically important for myelomagenesis, are also regulated by PDPK1, presumably through RSK2-NTKD (1, 2, 25, 33), whereas proapoptotic BIM and BAD, which are essential for apoptosis of hematopoietic cells, are negatively regulated by PDPK1 through the activation of ERK/RSK2 with or without AKT activation.…”

“…Our study showed that normal lymphocytes were much less sensitive to BX-912 compared with myeloma cells, and PDPK1 inhibition led to no life-threatening deleterious effect in several clinical trials for human and preclinical studies with animals (40,43,47). For instance, previous study has shown that PDPK1 hypomorphic mice expressing only 10% of the normal level of PDPK1 were viable, fertile, and exhibited no obvious harmful phenotype (48).…”

“…First, PDPK1 regulates two pivotal cell signaling molecules, RSK2-NTKD and AKT, and, thereby, controls the activity of molecules that are essential for disease development, proliferation, and survival in myeloma cells. For instance, PDPK1 regulates the activity of PLK1, which may be associated with cell division and the expression of c-MYC (43). Indeed, PDPK1 inhibition caused G 2 -M cell-cycle arrest in myeloma cells.…”

SCPattern: A statistical approach to identify and classify expression changes in single cell RNA-seq experiments with ordered conditions

“…In particular, cell cycle regulators MYCN and PLK1 were detected as EE-EE-EE-Down-EE (Figure 6(a)). This indicates a change of cell-cycle regulation during definitive endoderm cell differentiation (Tan et al, 2013). Additional classification results may be found in Supplementary Note section 3.…”