Oral Squamous Cell Carcinoma (OSCC) is the sixth most common human malignancy worldwide. Metabolic reprogramming is one of the hallmarks of cancer, and metabolic change favors rapid energy production and biosynthetic capabilities. The energy adaptation pathways promote tumor cells to survive, proliferation, and metastasis, which may be induced by hypoxia, free radicals, and nutrient depletion from microenvironment. The stresses of microenvironment also cause cancer cell autophagy, which is the major way to escape from cell death. Thus, many metabolic enzymes have become potential targets for new cancer therapies. Uncovering the intrinsic and extrinsic mechanisms that control the maintenance of cancer metabolism and autophagy is critical for developing novel therapeutic strategies to target cancer progression and recurrence.
Keywords: Oral squamous cell carcinoma; Cancer metabolism; Mitochondrion; Autophagy
OSCC is one of the 10 most frequent cancers worldwide [1-3], and five-year survival rate is less than 50% . The reason of high mortality in OSCC is metastasis, a process that cancer cells spread from a primary site and form tumors at proximal lymph nodes or distant sites [4-8]. Metabolic reprogramming plays crucial roles in cancer progression, including metastasis. Tumor cells exhibit an altered metabolism that is characterized by elevated uptake of glucose and increased glycolytic rate; this observation was first reported by Otto Warburg . Cancer cells generated the majority of ATP by glycolysis, even when grown in the presence of oxygen. However, recent studies have revealed the additional energy generation dependent on mitochondrial biogenesis .To addresses this issue; we aim to review the cancer metabolism and autophagy in OSCC progression. How does cancer cells adapt to microenvironment by using biogenetic reprogramming as a cell survival strategy? How does biogenetic reprogramming modulate a series of oncogenic and/or tumor suppressive signaling pathways? Understanding the metabolic pathways in tumors could contribute to the identification of novel therapeutic target and the development of more effective cancer therapeutic.
Cancer metabolism in microenvironment
Glycolysis and mitochondrial Oxidative Phosphorylation (OXPHOS) are the two main metabolic pathways to generate ATP. Glycolysis produces pyruvate which moving into the mitochondria converts to Acetyl-coenzyme A (acetyl-CoA), then enter the Tricarboxylic Acid (TCA) cycle and OXPHOS, generated up to 36 ATPs upon complete oxidative of one glucose molecule . During OXPHOS, oxygen is reduced to water in mitochondrial Electron Transport Chain (ETC). Under the hypoxia conditions, pyruvate is converted to lactate which completes glycolysis cycle and triggers Warburg effect. As the early tumor expands, cancer cells are exposed to hypoxia condition. Consequently, tumor hypoxia is a poor prognostic factor in malignancy [13-15]. Hypoxia-inducible factor- 1a (HIF-1a) is a transcription factor that increases glycolytic capacity and decreases mitochondrial respiration in OSCC [16,17]. Decreased dependence on aerobic respiration becomes advantageous to tumor cells. It also stimulates angiogenesis by up regulating Vascular Endothelial Growth Factor (VEGF) . Under normoxic conditions, the protein is tightly controlled by ubiquitin-dependent degradation; binding to the von Hippel-Lindau (pVHL) tumor suppressor protein . Loss of VHL expression was closely associated with pathologic grading, lymph node metastasis, poor prognosis, and EMT in OSCC . HIF-1a binds to pVHL only after it is hydroxylated by HIF Prolyl hydroxylase (PHD1) [21-23] and acetylated by Arrest-defective 1 protein (ARD1) acetyltransferase . This posttranslational modification (i.e., hydroxylation and acetylation) of HIF-1a protein promotes its association with pVHL and subsequent degradation [25-27]. The Warburg effect that is, an uncoupling of glycolysis from oxygen levels, cannot be explained solely by upregulation of Glycolysis and mitochondrial Oxidative Phosphorylation (OXPHOS) are the two main metabolic pathways to generate ATP. Glycolysis produces pyruvate which moving into the mitochondria converts to Acetyl-coenzyme A (acetyl-CoA), then enter the Tricarboxylic Acid (TCA) cycle and OXPHOS, generated up to 36 ATPs upon complete oxidative of one glucose molecule . During OXPHOS, oxygen is reduced to water in mitochondrial Electron Transport Chain (ETC). Under the hypoxia conditions, pyruvate is converted to lactate which completes glycolysis cycle and triggers Warburg effect. As the early tumor expands, cancer cells are exposed to hypoxia condition. Consequently, tumor hypoxia is a poor prognostic factor in malignancy [13-15]. Hypoxia-inducible factor- 1a (HIF-1a) is a transcription factor that increases glycolytic capacity and decreases mitochondrial respiration in OSCC [16,17]. Decreased dependence on aerobic respiration becomes advantageous to tumor cells. It also stimulates angiogenesis by up regulating Vascular Endothelial Growth Factor (VEGF) . Under normoxic conditions, the protein is tightly controlled by ubiquitin-dependent degradation; binding to the von Hippel-Lindau (pVHL) tumor suppressor protein . Loss of VHL expression was closely associated with pathologic grading, lymph node metastasis, poor prognosis, and EMT in OSCC . HIF-1a binds to pVHL only after it is hydroxylated by HIF Prolyl hydroxylase (PHD1) [21-23] and acetylated by Arrest-defective 1 protein (ARD1) acetyltransferase . This posttranslational modification (i.e., hydroxylation and acetylation) of HIF-1a protein promotes its association with pVHL and subsequent degradation [25-27]. The Warburg effect that is, an uncoupling of glycolysis from oxygen levels, cannot be explained solely by upregulation of 1a. These oxygen-independent mechanisms to activate oncogenesis tumor suppressor genes still need further investigations.
Important signaling pathways in OSCC metabolism
Cancer progression is dependent on the reprogramming of metabolism. Not only may the tumor microenvironment select for altered metabolic pathways, but also can oncogenes drive metabolic changes. The signaling molecule, Ras, a powerful oncogene when mutated, promotes glycolysis [28,29]. Ras was also confirmed as a direct target of miR-206, an important regulator in OSCC to reduce proliferation and invasion/migration . The phosphoinositide 3-kinase (PI3K) is one of the most activated signaling pathways, which links oncogenesis and glucose metabolism in OSCC [31,32]. Mutations in PI3K could provide strong growth and survival signals to tumor cells, and contribute to oncogene activation of the AKT pathway [33,34]. AKT1 is the crucial driver of the aerobic glycolysis pathway to stimulate ATP production, which ensures cells that have bioenergetic capacity to respond to growth signals [35,36]. AKT1 stimulates glycolysis by increasing the membrane translocation of glucose transporters and phosphorylating key glycolytic enzymes, such as hexokinase II (HK II) and Phosphofructokinase 2 (PFK2) [37,38]. In addition to its well-described roles in controlling cell growth and proliferation, the downstream transcription factor, Myc, also has several important effects on OSCC metabolism [39,40], including glutaminolysis . It may predict OSCC patients with poor prognosis . Regulation of metabolism is involved in tumor suppressors, such as p53 . p53 inhibits the glycolytic pathway by declined the transcription activity of the glucose transporter 1 (GLUT1) . Loss of the tumor suppressor protein p53 resulted in Warburg effect. Clinically, numbers of OSCC patients have p53 mutation . Taken together, tumor microenvironment may induce or interact oncogenes and tumor suppressor genes to drive metabolic shifts resulted in OSCC initiation, development, and progression.
Key enzymes of glucose metabolism in OSCC
Glucose is the major source of energy for cells, and GLUT1 is the most important transporter to facilitate the glucose transportation crossing the plasma membranes in humans . GLUT1 is aberrantly expressed in several tumor types. Studies have implicated its expression as a prognostic and diagnostic marker in OSCC clinically . Reduction of VHL  and miR-340  playas the switches to contribute the glucose uptake in OSCC by regulating GLUT1 expression.HK are a family of enzymes that catalyze the first phosphorylation of glucose to glucose-6-phosphate.HK II binds to mitochondria is via the outer membrane protein known as the voltage-dependent anion channel VDAC . It has been shown that high expression of HK II correlated with poor prognosis in OSCC, and the precise mechanism is still under investigation [51-52]. PKM2 is involved in OSCC initiation and progression by promoting cell proliferation and migration, and reducing apoptosis critically. Overexpression of PKM2 correlates with aggressive clinicopathological features and poor patients’ clinical outcome . In cancer metabolism, lactate is also important in glucose pathway. Lactate is made from pyruvate by lactate dehydrogenase (LDH) enzyme. In tumor microenvironment, excess lactate is secreted, and contributes to an extracellular environment to promote OSCC progression . The key enzyme, LDH, plays as a potential diagnostic marker and therapeutic index in OSCC [55,56]. Collectively, these studies support a model that metabolites, like lactate, facilitate malignant cancer development and metastasis, and could be the potential targets therapeutically in the future.
The role of mitochondria in cancer metabolism
The traditional view of cancer metabolism relying on glycolysis is due to mitochondrial dysfunction. However, the role of mitochondrial metabolism in modulating cancer progression is developed. Recent studies indicated that mitochondrial activity is essential for cancer cells. Mitochondrion plays important roles as energetic centers. Increased mitochondrial biogenesis promotes tumorigenesis, and loss of Mitochondrial DNA (mtDNA) copy number leads to decrease tumorigenesis due to OXPHOS impairment . Many evidence showed that elevated OXPHOS and mitochondrial activity is associated with cancer aggressiveness. As we know, mitochondrial transcription factor A (mtTFA/TFAM) is necessary for mtDNA maintenance, mitochondrial function and morphology [58-60]. Recent studies indicated that mtTFA significantly correlates to cancer behavior [61,62]. Its expression also highly associated with tumor progression and poor prognosis of patients with endometrial adenocarcinoma , and colorectal adenocarcinoma . Loss of mtTFA also inhibited Kras-mediated lung tumorigenesis . Enhanced mitochondrial biogenesis via mtTFA results in aberrant cell proliferation in arsenical skin cancer [66-67]. These data indicate that increased mtTFA may provide more energy for cancer progression. In our preliminary study, we found that advanced invasive OSCC cells, such as SAS and CA922 cells, showed more elevated oxygen consumption rate than less motility cells, including TW2.6 and Cal27 (Figure 1).
Figure 1: Mitochondrial metabolism is related to malignant behavior in OSCC cell lines. The basal oxygen consumption rate was determinate with a Seahorse XF24 analyzer. The experiment was performed at least 6 times. Error bar indicates S.D. value.
Although tumor cells prefer to use glycolysis as major bioenergetic pathway in the presence of oxygen, OXPHOS still play a crucial role in cancer progression. Mitochondrial gene-knockout B16 cells showed delayed subcutaneous tumor growth and failed to form lung tumors. The results suggest that mitochondrial function is required for tumor metastasis . p32/gC1qR/C1QBP/HABP1 is a mitochondrial protein over expressed in certain cancer cells. Fogal V et al. showed that knocked-down p32 expression in human cancer cells strongly shifts their metabolism from OXPHOS to glycolysis. The p32-knockdown cells exhibited reduced synthesis of the mtDNAFigure encoded OXPHOS polypeptides and less tumorigenicity in vivo. The results indicate that tumor cells may use p32 to regulate the balance between OXPHOS and glycolysispathways .
Forkhead box O transcription factors (FOXOs) show tumor suppressor function, which are the typical downstream effectorsinPI3K/AKT pathway, and are key regulators of cell cycle, apoptosis and response to oxidative stress . FOXO3a activation results in the nuclear-encoded genes repression of mitochondrial function, and a reduction in mtDNA copy number, mitochondrial respiratory complexes, and respiratory activity . Moreover, Myc could increase mitochondrial biogenesis and functions [72-75]. Mutation or knockdown of p53 promotes mitochondrial biogenesis . These results all suggested that mitochondrial function is essential for tumor formation and progression.
Autophagy as a therapeutic target
Autophagy is an evolutionarily conserved mechanism to adapt adverse microenvironment, including hypoxia, low pH, free radicals, and nutrient depletion. Several energetic sensors, such as AMPactivated protein kinase and mTOR, interacting with autophagy have evolved in metabolism [77,78]. Autophagy is involved in the formation of autophagosomes, and these structures subsequently fuse with lysosomes to form autolysosomes. Then they are delivered for degradation and recycling to maintain cellular homeostasis [79- 84]. This is attributed to promote cell survival under conditions of poor nutrient supply or oxidation stress, which are often faced by solid tumors and metastatic cancer cells. Dysregulation of autophagy has been reported in various human cancers, including OSCC. The autophagy-associated proteins were linked to malignancy and an unfavorable prognosis in OSCC . Beclin 1 takes part in the development of autophagy, and potentially plays an important role in the crosstalk between apoptosis and autophagy in OSCC cells . Another pivotal protein, autophagy-related 16-like 1 (ATG16L1), is essential for autophagosome formation. The present study suggested that ATG16L1 may be used as an aggressive phenotype biomarker for OSCC patients, and autophagy impairment contributed to cancer progression . These findings imply that autophagy inhibitors should be developed as a potential agent for adjuvant therapy in OSCC. Taken together, multiple molecular mechanisms induced by microenvironment converging to core cellular metabolism may provide support for ATP generation to maintain energy status, which results in OSCC progression (Figure 2). Increasing evidence indicate that inhibiting autophagy enhances the efficacy of cancer therapies by abolishing resistance and increasing cancer cell death. Since autophagy is often a pro-survival response to radiotherapy, chemotherapy, and target therapy drugs [88-98], suppression of autophagy during ant-cancer therapy has been proposed as a novel therapeutic strategy (Table 1). Therefore, development of new types of autophagy inhibitor for the treatment of cancer has important clinical significance.
Breast cancer and OSCC88,89
Esophageal cancer and OSCC90,91
Breast cancer and OSCC92,93
Thymidylate synthase inhibitor
CRC and OSCC91-94
EGFR tyrosine kinase inhibitor
NSCLC and OSCC95,96
EGFR monoclonal antibody
NSCLC and OSCC97,98
Table 1: Effects of cancer treatment on autophagy in preclinical studies.
Figure 2: The correlation of tumor metabolism and microenvironment. The metabolic phenotype of OSCC cells is controlled by genetic mutations responding to tumor microenvironment. Abnormal microenvironment conditions, such as hypoxia, low pH, high ROS level, and nutrient depletion elicit reactions from tumor cells, including autophagy. Oncogetic signaling pathways controlling growth and survival often activated by oncoproteins (such as Ras, PI3K, AKT, and Myc) or loss of tumor suppressors (such as p53). The results modify cellular metabolism reflecting to cellular bioenergetics and cancer progression.
Cancer cells display multiple metabolic alterations to affect proliferation and progression through dysregulation of oncogenes or tumor suppressors in microenvironment. The studies reviewed here suggest a unity in genes, mitochondria, and metabolic enzymes involved in OSCC, includingHIF-1a, Ras, PI3K, AKT, Myc, p53, mtTFA, GLUT1, HK II, PKM2, and LDH. While unfriendly microenvironment faced by cancer cells, autophagy is an extremely strategy to regulate tumor metabolism. Successful targeting of autophagy in cancer therapy may require molecular basis of distinct components of autophagy, as well as their interactions with other cellular and metabolic processes. The information provided here will be the basis of significant researches to fully clarify OSCC metabolism and potential targets in the future.
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Citation:Lai WT, Wu TS , Li YJ and Cheng CC. Metabolic Reprogramming in Oral Squamous Cell Carcinoma. J Dent & Oral Disord. 2016; 2(1): 1007. ISSN:2572-7710