Oncogenic Metabolism Acts as a Prerequisite Step for Induction of Cancer Metastasis and Cancer Stem Cell Phenotype

Abstract

Metastasis is a major obstacle to the efficient and successful treatment of cancer. Initiation of metastasis requires epithelial-mesenchymal transition (EMT) that is regulated by several transcription factors, including Snail and ZEB1/2. EMT is closely linked to the acquisition of cancer stem cell (CSC) properties and chemoresistance, which contribute to tumor malignancy. Tumor suppressor p53 inhibits EMT and metastasis by negatively regulating several EMT-inducing transcription factors and regulatory molecules; thus, its inhibition is crucial in EMT, invasion, metastasis, and stemness. Metabolic alterations are another hallmark of cancer. Most cancer cells are more dependent on glycolysis than on mitochondrial oxidative phosphorylation for their energy production, even in the presence of oxygen. Cancer cells enhance other oncogenic metabolic pathways, such as glutamine metabolism, pentose phosphate pathway, and the synthesis of fatty acids and cholesterol. Metabolic reprogramming in cancer is regulated by the activation of oncogenes or loss of tumor suppressors that contribute to tumor progression. Oncogenic metabolism has been recently linked closely with the induction of EMT or CSC phenotypes by the induction of several metabolic enzyme genes. In addition, several transcription factors and molecules involved in EMT or CSCs, including Snail, Dlx-2, HIF-1α, STAT3, TGF-β, Wnt, and Akt, regulate oncogenic metabolism. Moreover, p53 induces metabolic change by directly regulating several metabolic enzymes. The collective data indicate the importance of oncogenic metabolism in the regulation of EMT, cell invasion and metastasis, and adoption of the CSC phenotype, which all contribute to malignant transformation and tumor development. In this review, we highlight the oncogenic metabolism as a key regulator of EMT and CSC, which is related with tumor progression involving metastasis and chemoresistance. Targeting oncometabolism might be a promising strategy for the development of effective anticancer therapy.

Figure 1

DNA damage-induced senescence plays important roles in cancer development. DNA damage is induced by replication stress/telomere erosion, oxidative stress, and oncogene activation, which activate DNA damage response (DDR). DDR induces transient cell cycle arrest, apoptosis, and cellular senescence. DDR is mediated by checkpoint kinases ATM and ATR, which induce p53. In DDR, p53 induces the expression of many proapoptotic proteins including the BCL2 family (BAX, BID, PUMA, and NOXA) to induce apoptosis. In addition, p53 induces the expression of p21 which in turn activates RB tumor suppressor. p53, p21, and RB are involved in transient cell cycle arrest and cellular senescence. The p53-mediated cell cycle arrest, apoptosis, and cellular senescence act as tumor suppressive processes. Under transient cell cycle arrest, DNA damage is repaired by diverse DNA damage repair mechanisms. However, extensive DNA damage or insufficient repair by inactivation of DDR leads to genomic instability, then tumor-promoting growth factor (TPGF) and hypoxia contribute to cancer development and tumor progression. Senescent cells secrete senescence-associated secretory phenotype (SASP) proteins, consisting of growth factors, immunomodulatory chemokines and cytokines, extracellular matrix- (ECM-) remodeling proteases (matrix metalloproteinases), and ECM/insoluble proteins. The secreted cytokines induce an immune response. In addition, damaged DNA is recognized as a damage-associated molecular pattern (DAMP), triggering an immune response. Immune response inhibits cancer development at early stages, whereas it promotes cancer development at later stages. Furthermore, senescent cells exhibit increased glycolysis, which is regulated by the counterbalance of p53 and RB. Finally, SASP induces EMT, invasion, metastasis, and angiogenesis that are crucial for tumor progression.

Figure 2

Oncogenic metabolism plays an important role in the regulation of EMT. Four main mechanisms are involved in oncogenic metabolism-induced EMT: (1) regulation of both EMT and oncogenic metabolism by several transcription factors, (2) regulation of EMT by oncogenic enzymes and metabolites, (3) negative regulation of p53 by oncogenic metabolism, and (4) regulation of ROS and NADPH generation by oncogenic metabolism. (1) Several transcription factors and signaling factors involved in EMT or CSCs, including Snail, Dlx-2, HIF-1α, STAT3, TGF-β, Wnt, EGF, Notch, Hedgehog, hypoxia, and ROS, have been shown to regulate oncogenic metabolism. (2) PKM2 is translocated to the nucleus and then directly interacts with TGF-β-induced factor homeobox 2 (TGIF2) in colon cancer cells, thereby recruiting histone deacetylase 3 (HDAC3) to suppress E-cadherin transcription. PKM2 can also enhance tumor migration via PI3K/Akt signaling in gastric cancer. A FASN-TGF-β1-FASN-positive loop leads to high EMT/metastatic potential in cisplatin-resistant cancer cells. Furthermore, oncometabolites contribute induction of EMT. IDH1/2 mutations that induce the accumulation of 2-HG lead to EMT by ZEB1 upregulation and miR-200 downregulation in breast tumors and in colorectal cancer cells. The high levels of D-2-HG positively regulate the expression of ZEB1 in colorectal cancer cell, thereby inducing EMT. (3) Glutamine metabolism has been shown to downregulate p53 levels. Glutamine metabolism inhibition increases p53 expression and then induces the p53-dependent upregulation of Snail-targeting microRNAs, thereby leading to EMT induction by decreasing Snail mRNA levels. In addition, the abnormal TCA cycle enzymes, such as IDH mutants, prevent p53 activities. (4) Mutations of IDH, SDH, and FH induce ROS production. ROS play an important role in EMT. IDH mutation inhibits the production of NADPH and increases the consumption of NADPH. FH mutation also decreases NADPH levels by accumulation of fumarate. NADPH homeostasis plays an important role in the survival of cancer cells.