PDK1 signaling toward PLK1-MYC activation confers oncogenic transformation, tumor-initiating cell activation, and resistance to mTOR-targeted therapy.

Abstract

UNLABELLED:

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 findings 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 identifies 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 findings provide important insights into cancer and CSC biology and have significant therapeutic implications.

• Authors: Jing Tan, Zhimei Li, Puay Leng Lee, Peiyong Guan, Mei Yee Aau, Shuet Theng Lee, Min Feng, Cheryl Zihui Lim, Eric Yong Jing Lee, Zhen Ning Wee, Yaw Chyn Lim, R K Murthy Karuturi, Qiang Yu
• Journal: Cancer discovery (Cancer Discov) Vol. 3 Issue 10 Pg. 1156-71 (Oct 2013) ISSN: 2159-8290 [Electronic] United States
• PMID: 23887393 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• MYC protein, human
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-myc
• MTOR protein, human
• 3-Phosphoinositide-Dependent Protein Kinases
• PDPK1 protein, human
• Protein Serine-Threonine Kinases
• TOR Serine-Threonine Kinases
• polo-like kinase 1

Topics

• 3-Phosphoinositide-Dependent Protein Kinases (genetics, metabolism)
• Cell Cycle Proteins (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival (genetics)
• Cell Transformation, Neoplastic
• Colorectal Neoplasms (drug therapy)
• Drug Resistance, Neoplasm
• Humans
• Molecular Targeted Therapy
• Neoplastic Stem Cells (physiology)
• Phosphorylation
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Proto-Oncogene Proteins (genetics, metabolism)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)