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PDK1 Signaling Towards PLK1-Myc Activation Confers Oncogenic Transformation and Tumor Initiating Cell Activation and Resistance to Mtor-Targeted Therapy

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PDK1 Signaling Towards PLK1-Myc Activation Confers Oncogenic Transformation and Tumor Initiating Cell Activation and Resistance to Mtor-Targeted Therapy Author Manuscript Published OnlineFirst on July 25, 2013; DOI: 10.1158/2159-8290.CD-12-0595 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. PDK1 Signaling Towards PLK1-Myc Activation Confers Oncogenic Transformation and Tumor Initiating Cell Activation and Resistance to mTOR-targeted Therapy Jing Tan1, Zhimei Li1, Puay Leng Lee1, Peiyong Guan2, Mei Yee Aau1, Shuet Theng Lee1, Min Feng1, Cheryl Zihui Lim1, Eric Yong Jing Lee1, Zhen Ning Wee1,3 Yaw Chyn Lim4, R. K. Murthy Karuturi2 and Qiang Yu1, 4, 5,* 1 Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore. 2 Information and Mathematical Science, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore. 3Graduate School for Integrative Sciences and Engineering, National University of Singapore 4Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore 5Cancer and Stem Cell Biology, DUKE-NUS Graduate Medical School of Singapore Running Title: PDK1- PLK1-Myc signaling in transformation, cancer stem cells and drug resistance. *Correspondence: [email protected] Qiang Yu, M.D. Ph.D. Cancer Therapeutics and Stratified Oncology Genome Institute of Singapore Email: [email protected] Fax: 65-6808-9003 Disclosure of Potential Conflicts of Interest No potential conflicts of interests were disclosed. 1 Downloaded from cancerdiscovery.aacrjournals.org on September 27, 2021. © 2013 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 25, 2013; DOI: 10.1158/2159-8290.CD-12-0595 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ABSTRACT Although 3-Phosphoinositide–dependent protein kinase-1 (PDK1) has been predominately linked to 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 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 PLK1 inhibitor synergizes with mTOR inhibitor to induce synergistic anti-tumor effect in colorectal cancer by antagonizing a 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 cancer stem cell 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 cancer stem cell biology and have significant therapeutic implications. 2 Downloaded from cancerdiscovery.aacrjournals.org on September 27, 2021. © 2013 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 25, 2013; DOI: 10.1158/2159-8290.CD-12-0595 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. INTRODUCTION Phosphatidylinositol 3’-kinase (PI3K)-AKT pathway is one of the most commonly deregulated signaling pathways in human cancers (1). Genetic aberrations affecting this pathway, such as activating mutations of PIK3CA or inactivation of PTEN, have been identified in virtually all epithelial tumors (2). The 3-phosphoinositide-dependent protein kinase-1 (PDK1) is known to be activated as a result of the accumulation of the PI3K product phosphatidylinositol-3,4,5-trisphosphate (PIP3) and thus considered as an important component of the PI3K pathway. PDK1 is a master regulator of AGC kinase members, including AKT, p70 ribosomal S6 kinase (S6K), serum- and glucocorticoid- induced protein kinase (SGK) and protein kinase C (PKC) family members, thus having multiple roles in various physiological processes such as metabolism, growth, proliferation and survival (3). In human cancers, PDK1 is thought to be constitutively activated upon elevation of PIP3 owing to the loss of PTEN or gain of PIK3CA activity. In addition, PDK1 deregulation in human malignancy can also be caused by gene amplification or abnormal phosphorylation in cytosol and nucleus, such as colon cancer and invasive breast cancer (4, 5). One of the most defined PDK1 targets relevant in human cancer is AKT. Specifically, PDK1 directly phosphorylates AKT on T308, but requires mTORC2- induced AKT phosphorylation on S473 to confer a full activation (6). Given its connection to AKT, PDK1 has been pursued as a critical anti-cancer target (7). However, in view of the diversity of PDK1 substrates, additional downstream targets of PDK1 may confer aberrant signaling heterogeneity and complexity in human malignance. Indeed, it has been recently shown that inhibition of PDK1 has no significant effect on AKT 3 Downloaded from cancerdiscovery.aacrjournals.org on September 27, 2021. © 2013 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 25, 2013; DOI: 10.1158/2159-8290.CD-12-0595 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. signaling in a PTEN-deficient transgenic tumor mouse model (8) or breast tumor growth (9), and oncogenic functions of PDK1 through substrates other than AKT, such as SGK3 (10), MAPK (11), or PKC (12), have also been reported. In addition, our recent work has shown that PDK1 is required for Myc protein accumulation in colon cancer cells treated with mTOR inhibitor rapamycin (5), indicating a potential functional link of PDK1 with Myc in oncogeneiss. Myc is implicated in both cancer and stem cell self-renewal. The relationship between stem cell and human cancers has become an important issue in cancer research given that self-renewal is a hallmark of both cell types (13). Genes associated with embryonic stem cell (ESC) identity, including pluripotency transcription factors, Polycomb targets and Myc targets, have been observed in aggressive human cancers and are associated with poor disease outcome (14). Moreover, the Myc associated molecular network is strikingly similar between ESC and human cancer transcription programs (15), and ectopic overexpression of Myc in differentiated somatic cells can induce both ESC gene signature and properties of cancer stem cells (CSC) (16). These findings suggest that activation of an ESC-like gene expression program in adult cells may confer self- renewal to cancer cells or cancer stem cells. Notably, although the cancer associated ESC–like gene regulation by transcription factors has been well documented, its regulation by a druggable kinase-driven signaling pathway has yet to be identified. In the present studies, we investigated PDK1-evoked key signaling events required for oncogenic transformation. We identified that PDK1-PLK1-Myc pathway is a major driver pathway conferring PDK-induced transformation and its existence is readily evident in human cancers. We further show that PDK1-PLK1-Mys signaling drives an 4 Downloaded from cancerdiscovery.aacrjournals.org on September 27, 2021. © 2013 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 25, 2013; DOI: 10.1158/2159-8290.CD-12-0595 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ESC-like gene expression signature relevant in human cancers and is robust in inducing CSC phenotype. It also involves in resistance to mTOR inhibitor in colorectal cancer cells. These findings provide important insights into the cancer and cancer stem cell biology and potential new treatment for targeting Myc-dependency in human cancers RESULTS PDK1-Induced Myc Protein Induction Confers Oncogenic Transformation As the first step to investigate the differential signaling pathways activated by PDK1 or PI3K in tumorigenesis, we compared the transforming capacity of PDK1 and PI3K by using the in vitro transformation assay that measures the anchorage-independent growth in soft agar. We began with semi-transformed human embryonic kidney epithelial cells (HEK) that express a low level of activated HRasV12 (HEK-TERV)(17) and infected them with retroviral vectors expressing PDK1, Myc, a constitutively activating mutant of PIK3CA (E545K) or PTEN small hairpin RNA (shRNA), resulting in stable cell lines designated as HEK-PDK1, HEK-Myc, HEK-E545K or HEK-shPTEN cells, respectively. The transformation assay results showed that they were all able to induce cellular transformation, although PDK1- or Myc-induced colonies appeared to be larger in size as compared with that of E545K- or shPTEN-expressing cells (Fig. 1A and Supplementary Fig. S1A). Consistent with our previous report showing a post-translational Myc induction by PDK1 (5), we detected a marked protein accumulation of Myc in HEK- PDK1 cells but not in HEK-E545K or HEK-shPTEN cells (Fig. 1B) which was not due to the induction of Myc mRNA level (Supplementary Fig. S1B). We also show that the kinase activity
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