title: Preclinical development of a bifunctional cancer cell homing, PKCepsilon inhibitory peptide for the treatment of head and neck cancer.
abstract: Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent cancer worldwide, comprising approximately 50% of all malignancies in some developing nations. Our recent work identified protein kinase Cepsilon (PKCepsilon) as a critical and causative player in establishing an aggressive phenotype in HNSCC. In this study, we investigated the specificity and efficacy of HN1-PKCepsilon, a novel bifunctional cancer cell homing, PKCepsilon inhibitory peptide, as a treatment for HNSCC. HN1-PKCepsilon peptide was designed by merging two separate technologies and synthesized as a capped peptide with two functional modules, HN1 (cancer cell homing) and PKCepsilon (specific PKCepsilon inhibitory), connected by a novel linker module. HN1-PKCepsilon preferentially internalized into UMSCC1 and UMSCC36 cells, two HNSCC cell lines, in comparison with oral epithelial cells: 82.1% positive for UMSCC1 and 86.5% positive for UMSCC36 compared with 1.2% positive for oral epithelial cells. In addition, HN1-PKCepsilon penetrated HNSCC cells in a dose- and time-dependent manner. Consistent with these in vitro observations, systemic injection of HN1-PKCepsilon resulted in selective delivery of HN1-PKCepsilon into UMSCC1 xenografts in nude mice. HN1-PKCepsilon blocked the translocation of active PKCepsilon in UMSCC1 cells, confirming HN1-PKCepsilon as a PKCepsilon inhibitor. HN1-PKCepsilon inhibited cell invasion by 72 +/- 2% (P < 0.001, n = 12) and cell motility by 56 +/- 2% (P < 0.001, n = 5) in UMSCC1 cells. Moreover, in vivo bioluminescence imaging showed that HN1-PKCepsilon significantly (83 +/- 1% inhibition; P < 0.02) retards the growth of UMSCC1 xenografts in nude mice. Our work indicates that the bifunctional HN1-PKCepsilon inhibitory peptide represents a promising novel therapeutic strategy for HNSCC.
authors: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors: Liwei
authors: L
authors: Bao
authors: Michael A
authors: MA
authors: Gorin
authors: Manchao
authors: M
authors: Zhang
authors: Alejandra C
authors: AC
authors: Ventura
authors: William C
authors: WC
authors: Pomerantz
authors: Sofia D
authors: SD
authors: Merajver
authors: Theodoros N
authors: TN
authors: Teknos
authors: Anna K
authors: AK
authors: Mapp
authors: Quintin
authors: Q
authors: Pan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C543811:HN1-PKCepsilon peptide; D010455:Peptides; D051744:Protein Kinase C-epsilon