Metformin and Cancer Hallmarks: Molecular Mechanisms in Thyroid, Prostate and Head and Neck Cancer Models

Abstract

Metformin is the most used drug for type 2 diabetes (T2DM). Its antitumor activity has been described by clinical studies showing reduced risk of cancer development in T2DM patients, as well as management of T2DM compared with those receiving other glucose-lowering drugs. Metformin has a plethora of molecular actions in cancer cells. This review focused on in vitro data on the action mechanisms of metformin on thyroid, prostate and head and neck cancer. AMPK activation regulating specific downstream targets is a constant antineoplastic activity in different types of cancer; however, AMPK-independent mechanisms are also relevant. In vitro evidence makes it clear that depending on the type of tumor, metformin has different actions; its effects may be modulated by different cell conditions (for instance, presence of HPV infection), or it may regulate tissue-specific factors, such as the Na⁺/I^- symporter (NIS) and androgen receptors. The hallmarks of cancer are a set of functional features acquired by the cell during malignant development. In vitro studies show that metformin regulates almost all the hallmarks of cancer. Interestingly, metformin is one of these therapeutic agents with the potential to synergize with other chemotherapeutic agents, with low cost, low side effects and high positive consequences. Some questions are still challenging: Are metformin in vitro data able to translate from bench to bedside? Does metformin affect drug resistance? Can metformin be used as a generic anticancer drug for all types of tumors? Which are the specific actions of metformin on the peculiarities of each type of cancer? Several clinical trials are in progress or have been concluded for repurposing metformin as an anticancer drug. The continuous efforts in the field and future in vitro studies will be essential to corroborate clinical trials results and to elucidate the raised questions.

Keywords: cancer; hallmarks; head and neck; in vitro; mechanisms; metformin; prostate; thyroid.

Figure 1

Pathways regulated by metformin in thyroid, prostate, and head and neck cancers. Blue targets show inhibited or downregulated, and red targets show activated or upregulated by metformin. Signaling molecules and arrows in gray have no direct relationship described with metformin. Acetyl-CoA carboxylase (ACC), AKT Serine/Threonine Kinase (AKT), AMPK (adenosine monophosphate-activated protein kinase), androgen receptor (AR), Androgen receptor variant 7(ARV7), Ataxia Telangiectasia Mutated (ATM), Ataxia Telangiectasia And Rad3-Related Protein (ATR), Na+/I- symporter (NIS), BCL2 Associated X, Apoptosis Regulator (BAX), Bcl-2 Interacting Mediator Of Cell Death (BIM), B-Cell CLL/Lymphoma 2 (BCL2), Binding-Immunoglobulin Protein (BIP), Cholinergic Receptor Nicotinic Alpha 7 Subunit (CHRNA7), C/EBP Homologous Protein (CHOP), cyclic AMP (cAMP), C-X-C motif chemokine receptor 4 (CXCR4), C-X-C Motif Chemokine Ligand 12 (CXCL12), Cyclooxygenase 2 (COX2), DNA-dependent protein kinase (DNA-PK), Endoplasmic reticulum (ER), Early Growth Response 2 (EGR2), Epithelial–mesenchymal transition (EMT), Eukaryotic Translation Initiation Factor 4E Binding Protein 1 (4EBP1), Extracellular Signal-Regulated Kinase 2 (ERK), Forkhead Box M1 (FOXM1), Glucose transporter 1 (Glut1), H2A.Z variant histone 1 (H2AZ1), Hexokinase-2 (HK2), Interleukin-6 (IL6), Interleukin-6 receptor (IL6R), Insulin Like Growth Factor 1 Receptor (IGF1R), Insulin Receptor Substrate (IRS), Janus Kinase (JAK), JUN N-Terminal Kinase (JNK), LDL Receptor Related Protein 2 (LRP2), X-Ray Repair Cross Complementing 6 (Ku70), X-Ray Repair Cross Complementing 5 (Ku80), Mammalian target of rapamycin (mTOR), MAPK/ERK Kinase 1 (MEK), Midline-1 (MID1), Mitochondrial GAPDH (mGPDH), MYC Proto-Oncogene, BHLH Transcription Factor (C-Myc), Neuronatin (NNAT), Nijmegen breakage syndrome 1 protein (NBS1), RAD50 Double Strand Break Repair (Rad50), Nuclear Factor Kappa B (NFκB), ZFP42 Zinc Finger (REX1), oxidative phosphorylation (OXPHOS), Pigment epithelium-derived factor (PEDF), Phosphoinositide 3-kinase (PI3K), Phosphatase And Tensin Homolog (PTEN), Proline, Glutamate And Leucine Rich Protein 1 (PELP1), Pyruvate Dehydrogenase Kinase 1 (PDK1), P53 Up-Regulated Modulator Of Apoptosis (PUMA),Raf-1 Proto-Oncogene, Serine/Threonine Kinase (RAF), Ras Proto-Oncogene GTPase (RAS), Regulated in development and DNA damage response 1 (REDD1), Ribosomal Protein S6 Kinase B1 (S6K1), Ribosomal protein S6 (S6), Small heterodimer partner–interacting leucine zipper (SMILE), Signal Transducer And Activator Of Transcription (STAT3), Transforming Growth Factor Beta 1 (TGF-β1), Tumor Necrosis Factor alpha 1 (TNF-α), S-adenosylhomocysteine (SAHH), Small Nucleolar RNA Host Gene 7 (SNHG7), Telomerase Reverse Transcriptase (TERT), TSC Complex Subunit 2 (TSC2), Twist Family BHLH Transcription Factor (TWIST), Vascular Endothelial Growth Factor (VEGF),YES1-associated transcriptional regulator (YAP).

Figure 2

Metformin and hallmarks of cancer, genes regulated directly or indirectly by metformin in thyroid prostate and head and neck cancer. Red genes: activated; blue genes: inhibited (9 modified). Acetyl-CoA carboxylase (ACC), AKT Serine/Threonine Kinase (AKT), AMPK (adenosine monophosphate-activated protein kinase), Ataxia Telangiectasia Mutated (ATM), Adenosine triphosphate (ATP), Ataxia Telangiectasia And Rad3-Related Protein (ATR), Na+/I- symporter (NIS), BCL2 Associated X, Apoptosis Regulator (BAX), Bcl-2 Interacting Mediator Of Cell Death (BIM), B-Cell CLL/Lymphoma 2 (BCL2), Binding-Immunoglobulin Protein (BIP), Cholinergic Receptor Nicotinic Alpha 7 Subunit (CHRNA7), C/EBP Homologous Protein (CHOP), cyclic AMP (cAMP), C-C Motif Chemokine Ligand 2 (CCL2), C-C Motif Chemokine Receptor 1 (CCR1), C-X-C Motif Chemokine Ligand 8 (CXCL8), C-X-C Motif Chemokine Ligand 12 (CXCL12), C-C Motif Chemokine Ligand 15 (CC15), C-X-C motif chemokine receptor 4 (CXCR4), Cyclooxygenase 2 (COX2), DNA-dependent protein kinase (DNA-PK), Eukaryotic Translation Initiation Factor 4E Binding Protein 1 (4EBP1), Extracellular Signal-Regulated Kinase 2 (ERK), Enhancer Of Zeste 2 Polycomb Repressive Complex 2 Subunit (EZH2), Forkhead Box M1 (FOXM1), Glucose transporter 1 (Glut1), H2A.Z variant histone 1 (H2AZ1), Hexokinase-2 (HK2), Hedgehog (Hh), NFκB Inhibitor Alpha (IκBακ), Inhibitor of nuclear factor kappa-B kinase subunit alpha/beta (Iκκα/β), Interleukin-6 (IL6), Interleukin -10 (IL-10), Interleukin-1 receptor alpha (IL1-Ra), Inducible nitric oxide synthase (iNOS), Interleukin-6 receptor (IL6R), Insulin Like Growth Factor 1 Receptor (IGF1R), Insulin Receptor Substrate (IRS), JUN N-Terminal Kinase (JNK), LDL Receptor Related Protein 2 (LRP2), X-Ray Repair Cross Complementing 6 (Ku70), X-Ray Repair Cross Complementing 5 (Ku80), Mammalian target of rapamycin (mTOR), MAPK/ERK Kinase 1 (MEK), Midline-1 (MID1), Mitochondrial GAPDH (mGPDH), Matrix Metallopeptidase 2 (MMP2), Matrix Metallopeptidase (MMP9), MYC Proto-Oncogene - BHLH Transcription Factor (C-Myc), Neuronatin (NNAT), Nijmegen breakage syndrome 1 protein (NBS1), RAD50 Double Strand Break Repair (Rad50), Nuclear Factor Kappa B (NFκB), Tumor Protein P53 (P53), Pigment epithelium-derived factor (PEDF), Phosphoinositide 3-kinase (PI3K), Pyruvate Kinase M1/2 (PKM2), Proline, Glutamate And Leucine Rich Protein 1 (PELP1), Receptor Activator Of Nuclear Factor Kappa B Ligand (RANKL), Regulated in development and DNA damage response 1 (REDD1), ZFP42 Zinc Finger (REX1), Ribosomal Protein S6 Kinase B1 (S6K1), Ribosomal protein S6 (S6), Small heterodimer partner–interacting leucine zipper (SMILE), Snail Family Transcriptional Repressor 1 (SNAIL), Sterol Regulatory Element Binding Transcription Factor 1 (SREBP1C), Signal Transducer And Activator Of Transcription (STAT3), SUV39H1 Histone Lysine Methyltransferase (SUV39H), Transforming Growth Factor Beta 1 (TGF-β1), S-adenosylhomocysteine (SAHH),), Telomerase Reverse Transcriptase (TERT),), Tartrate-Resistant Acid Phosphatase 5b (TRACP5b), Twist Family BHLH Transcription Factor (TWIST), Vascular Cell Adhesion Molecule (VCAM), Vascular Endothelial Growth Factor (VEGF),YES1-associated transcriptional regulator (YAP).