title: Prevention of tumor growth driven by PIK3CA and HPV oncogenes by targeting mTOR signaling with metformin in oral squamous carcinomas expressing OCT3.
abstract: Most squamous cell carcinomas of the head and neck (HNSCC) exhibit a persistent activation of the PI3K-mTOR signaling pathway. We have recently shown that metformin, an oral antidiabetic drug that is also used to treat lipodystrophy in HIV-infected (HIV(+)) individuals, diminishes mTOR activity and prevents the progression of chemically induced experimental HNSCC premalignant lesions. Here, we explored the preclinical activity of metformin in HNSCCs harboring PIK3CA mutations and HPV oncogenes, both representing frequent HNSCC alterations, aimed at developing effective targeted preventive strategies. The biochemical and biologic effects of metformin were evaluated in representative HNSCC cells expressing mutated PIK3CA or HPV oncogenes (HPV(+)). The oral delivery of metformin was optimized to achieve clinical relevant blood levels. Molecular determinants of metformin sensitivity were also investigated, and their expression levels were examined in a large collection of HNSCC cases. We found that metformin inhibits mTOR signaling and tumor growth in HNSCC cells expressing mutated PIK3CA and HPV oncogenes, and that these activities require the expression of organic cation transporter 3 (OCT3/SLC22A3), a metformin uptake transporter. Coexpression of OCT3 and the mTOR pathway activation marker pS6 were observed in most HNSCC cases, including those arising in HIV(+) patients. Activation of the PI3K-mTOR pathway is a widespread event in HNSCC, including HPV(-) and HPV(+) lesions arising in HIV(+) patients, all of which coexpress OCT3. These observations may provide a rationale for the clinical evaluation of metformin to halt HNSCC development from precancerous lesions, including in HIV(+) individuals at risk of developing HPV(-) associated cancers.
authors: Molecular Carcinogenesis Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland.
authors: Dmitri
authors: D
authors: Madera
authors: Molecular Carcinogenesis Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland.
authors: Lynn
authors: L
authors: Vitale-Cross
authors: Molecular Carcinogenesis Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland.
authors: Daniel
authors: D
authors: Martin
authors: Department of Oncology and Diagnostic Sciences, School of Dentistry and Greenebaum Cancer Center, Program in Oncology, University of Maryland, Baltimore, Maryland.
authors: Abraham
authors: A
authors: Schneider
authors: Molecular Carcinogenesis Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland.
authors: Alfredo A
authors: AA
authors: Molinolo
authors: Department of Pathology, Mahatma Gandhi Institute of Medical Sciences, Wardha, Maharashtra, India.
authors: Nitin
authors: N
authors: Gangane
authors: Department of Otolaryngology-Head Neck Surgery, and the Head and Neck SPORE Tissue Core, University of Michigan, Ann Arbor, Michigan.
authors: Thomas E
authors: TE
authors: Carey
authors: Department of Otolaryngology-Head Neck Surgery, and the Head and Neck SPORE Tissue Core, University of Michigan, Ann Arbor, Michigan.
authors: Jonathan B
authors: JB
authors: McHugh
authors: Department of Otolaryngology-Head Neck Surgery, and the Head and Neck SPORE Tissue Core, University of Michigan, Ann Arbor, Michigan.
authors: Christine M
authors: CM
authors: Komarck
authors: Department of Otolaryngology-Head Neck Surgery, and the Head and Neck SPORE Tissue Core, University of Michigan, Ann Arbor, Michigan.
authors: Heather M
authors: HM
authors: Walline
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: William N
authors: WN
authors: William
authors: University of Pittsburgh School of Medicine, Pathology Program, Pittsburgh, Philadelphia.
authors: Raja R
authors: RR
authors: Seethala
authors: Otolaryngology, Immunology, Cancer Immunology Program, University of Pittsburgh School of Medicine, Pittsburgh, Philadelphia.
authors: Robert L
authors: RL
authors: Ferris
authors: Molecular Carcinogenesis Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland. sg39v@nih.gov.
authors: J Silvio
authors: JS
authors: Gutkind
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016022:Case-Control Studies; D002453:Cell Cycle; D049109:Cell Proliferation; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D006258:Head and Neck Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D050814:Octamer Transcription Factor-3 / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D027383:Papillomaviridae / Q000502:physiology; D030361:Papillomavirus Infections / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D007004:Hypoglycemic Agents; D008687:Metformin; D050814:Octamer Transcription Factor-3; D009856:Oncogene Proteins, Viral; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; C494173:POU5F1 protein, human; C546842:MTOR protein, human; C484760:PIK3CA protein, human