Cannabinoids Promote Progression of HPV-Positive Head and Neck Squamous Cell Carcinoma via p38 MAPK Activation

Clin Cancer Res. 2020 Jun 1;26(11):2693-2703. doi: 10.1158/1078-0432.CCR-18-3301. Epub 2020 Jan 13.


Purpose: Human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) is associated with daily marijuana use and is also increasing in parallel with increased marijuana use in the United States. Our study is designed to define the interaction between cannabinoids and HPV-positive HNSCC.

Experimental design: The expression of cannabinoid receptors CNR1 and CNR2 was analyzed using The Cancer Genome Atlas (TCGA) HNSCC data. We used agonists, antagonists, siRNAs, or shRNA-based models to explore the roles of CNR1 and CNR2 in HPV-positive HNSCC cell lines and animal models. Cannabinoid downstream pathways involved were determined by Western blotting and analyzed in a primary HPV HNSCC cohort with single-sample gene set enrichment analysis (ssGSEA) and the OncoGenome Positioning System (Onco-GPS).

Results: In TCGA cohort, the expression of CNR1 and CNR2 was elevated in HPV-positive HNSCC compared with HPV-negative HNSCC, and knockdown of CNR1/CNR2 expression inhibited proliferation in HPV-positive HNSCC cell lines. Specific CNR1 and CNR2 activation as well as nonselective cannabinoid receptor activation in cell lines and animal models promoted cell growth, migration, and inhibited apoptosis through p38 MAPK pathway activation. CNR1/CNR2 antagonists suppressed cell proliferation and migration and induced apoptosis. Using whole-genome expression analysis in a primary HPV HNSCC cohort, we identified specific p38 MAPK pathway activation signature in tumors from HPV HNSCC patients with objective measurement of concurrent cannabinoid exposure.

Conclusions: Cannabinoids can promote progression of HPV-positive HNSCC through p38 MAPK pathway activation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Cannabinoids / pharmacology*
  • Cell Movement
  • Cell Proliferation
  • Female
  • Head and Neck Neoplasms / drug therapy
  • Head and Neck Neoplasms / metabolism
  • Head and Neck Neoplasms / pathology*
  • Head and Neck Neoplasms / virology
  • Humans
  • Mice
  • Mice, Nude
  • Papillomaviridae / isolation & purification*
  • Papillomavirus Infections / complications*
  • Papillomavirus Infections / drug therapy
  • Papillomavirus Infections / virology
  • Prognosis
  • Receptors, Cannabinoid / chemistry*
  • Receptors, Cannabinoid / metabolism
  • Squamous Cell Carcinoma of Head and Neck / drug therapy
  • Squamous Cell Carcinoma of Head and Neck / metabolism
  • Squamous Cell Carcinoma of Head and Neck / pathology*
  • Squamous Cell Carcinoma of Head and Neck / virology
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Cannabinoids
  • Receptors, Cannabinoid
  • p38 Mitogen-Activated Protein Kinases