Tumor quiescence: elevating SOX2 in diverse tumor cell types downregulates a broad spectrum of the cell cycle machinery and inhibits tumor growth

Abstract

Background Quiescent tumor cells pose a major clinical challenge due to their ability to resist conventional chemotherapies and to drive tumor recurrence. Understanding the molecular mechanisms that promote quiescence of tumor cells could help identify therapies to eliminate these cells. Significantly, recent studies have determined that the function of SOX2 in cancer cells is highly dose dependent. Specifically, SOX2 levels in tumor cells are optimized to promote tumor growth: knocking down or elevating SOX2 inhibits proliferation. Furthermore, recent studies have shown that quiescent tumor cells express higher levels of SOX2 compared to adjacent proliferating cells. Currently, the mechanisms through which elevated levels of SOX2 restrict tumor cell proliferation have not been characterized. Methods To understand how elevated levels of SOX2 restrict the proliferation of tumor cells, we engineered diverse types of tumor cells for inducible overexpression of SOX2. Using these cells, we examined the effects of elevating SOX2 on their proliferation, both in vitro and in vivo. In addition, we examined how elevating SOX2 influences their expression of cyclins, cyclin-dependent kinases (CDKs), and p27Kip1. Results Elevating SOX2 in diverse tumor cell types led to growth inhibition in vitro. Significantly, elevating SOX2 in vivo in pancreatic ductal adenocarcinoma, medulloblastoma, and prostate cancer cells induced a reversible state of tumor growth arrest. In all three tumor types, elevation of SOX2 in vivo quickly halted tumor growth. Remarkably, tumor growth resumed rapidly when SOX2 returned to endogenous levels. We also determined that elevation of SOX2 in six tumor cell lines decreased the levels of cyclins and CDKs that control each phase of the cell cycle, while upregulating p27Kip1. Conclusions Our findings indicate that elevating SOX2 above endogenous levels in a diverse set of tumor cell types leads to growth inhibition both in vitro and in vivo. Moreover, our findings indicate that SOX2 can function as a master regulator by controlling the expression of a broad spectrum of cell cycle machinery. Importantly, our SOX2-inducible tumor studies provide a novel model system for investigating the molecular mechanisms by which elevated levels of SOX2 restrict cell proliferation and tumor growth.

Effect of Tumor Red Blood Cell Immunity and Tumor Cell Cycle in Mice Bearing Solid Liver Cancer with Intelligent Cancer Zhongning Therapeutic Apparatus

“…At present, further breakthroughs have been made in the experimental study and analysis of the relationship between the expression, mechanism, regulatory mechanism, and disease of RBC immune function. dependent kinase inhibitor [16][17][18]. Cell cycle regulation is a complex biological process, which is related to the biological efficacy of protooncogenes and tumor suppressor genes.…”

“…In evolution, cells change and form a series of regulatory mechanisms to ensure the accurate and orderly exchange of the cell cycle. There are mainly three types of molecules related to cell cycle regulation: cyclin, cyclin-dependent kinase (CDK), cyclin-dependent kinase inhibitor [ 16 – 18 ]. Cell cycle regulation is a complex biological process, which is related to the biological efficacy of protooncogenes and tumor suppressor genes.…”

SOX2 mediates metabolic reprogramming of prostate cancer cells

“…SOX2 is clearly implicated in promoting lineage plasticity in prostate cancer, and multiple groups demonstrated an association between expression of SOX2 and neuroendocrine genes with onset of the neuroendocrine prostate cancer (NEPC) cancer phenotype [ 38 – 43 ]. A role for SOX2 as an oncogene is further supported by multiple studies demonstrating SOX2-mediated changes in cell growth, invasion, and chemoresistance across multiple tumor types [ 6 , 17 , 44 – 48 ]. Further, we and others have shown that SOX2 is sufficient to enable castration-resistant tumor growth and resistance to the AR antagonist enzalutamide [ 2 , 3 ].…”

Biomarkers of Cancer Stem Cells for Experimental Research and Clinical Application

“…For example, the introduction of SOX2 in prostate cancer induces stem-like characteristics but uses different metabolic pathways and interacts with different target gene products. The oncogenic role of SOX2 is confirmed further by several studies exhibiting SOX2 dependent alteration of cell growth, invasion ability, and chemo-resistant activity beyond tumor types [ 103 , 104 ]. de Wet et al demonstrated that most target genes of SOX2 regulation in prostate cancer are non-overlapping with targets of SOX2 in human ESCs, and identified different cis elements within what appear to be similar target genes.…”