Targeting PDK1 for Chemosensitization of Cancer Cells

Abstract

Despite the rapid development in the field of oncology, cancer remains the second cause of mortality worldwide, with the number of new cases expected to more than double in the coming years. Chemotherapy is widely used to decelerate or stop tumour development in combination with surgery or radiation therapy when appropriate, and in many cases this improves the symptomatology of the disease. Unfortunately though, chemotherapy is not applicable to all patients and even when it is, there are many cases where a successful initial treatment period is followed by chemotherapeutic drug resistance. This is caused by a number of reasons, ranging from the genetic background of the patient (innate resistance) to the formation of tumour-initiating cells (acquired resistance). In this review, we discuss the potential role of PDK1 in the development of chemoresistance in different types of malignancy, and the design and application of potent inhibitors which can promote chemosensitization.

Elevated PDK1 Expression Drives PI3K/AKT/MTOR Signaling Promotes Radiation-Resistant and Dedifferentiated Phenotype of Hepatocellular Carcinoma

“…In the present study, for the first time, to the best of our knowledge, we demonstrated that PDK1 is an independent driver of the PI3K/AKT/mTOR signaling pathway and its aberrant expression characterizes poorly differentiated aggressive HCC cells (Figure 1). This is consistent with reports indicating that while PDK1 oncogenic activities are not dependent on PI3K/AKT signaling, the later more often than not is modulated by PDK1 expression [23], and as rightly put by Tan J et al, while PDK1 is almost always linked with the PI3K/AKT signaling pathway, evidence abound that it does also induce other efferent oncogenic signaling, such as demonstrated by its unmediated induction of Polo-like kinase 1 (PLK1) phosphorylation, with subsequent activation and nuclear accumulation of MYC, resulting in the growth and survival of cancerous cells, induction of an embryonic stem cell (ESC)-like gene-signature, which is associated with aggressive cancer traits and robust CSC-driving signaling, as well as resistance to mTOR-targeted therapy [24]. More so, the characterization of poorly differentiated aggressive HCC cells by aberration in PDK1 expression is of clinical relevance, since it is broadly understood that poorly differentiated cancerous cells exhibit greater degree of resistance to therapy, and are strongly associated with increased metastasis and poor prognosis [25], thus, highlighting a critical role for PDK1 as a putative molecular target in HCC.…”

Phosphoinositide‐dependent Kinase‐1 (PDPK1) regulates serum/glucocorticoid‐regulated Kinase 3 (SGK3) for prostate cancer cell survival

“…42 However, recent studies have also shown that PDPK1 can activate many other members of AGC kinase family such as p70S6K, SGK, p90RSK and the members of PKC family, independent of AKT. [42][43][44] To evaluate whether the pro-…”

Causal integration of multi-omics data with prior knowledge to generate mechanistic hypotheses

“…It also predicted a depletion of adenine and consequently the down-regulation of PDPK1 activity through CXCR4 ( Figure 4A ). Footprint analysis showed a down-regulation of PDPK1 (that is, the abundance of phosphorylation on its direct target phosphosites is decreasing) activity, which is surprising since its expression is usually associated with slower proliferation of kidney tumor cells 43,44 . Yet, the observed coordinated depletion of adenine, hypoxanthine and inosine strongly support the estimated down-regulation of PDPK1 activity.…”