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.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent cancer worldwide
We reported that protein kinase Cε (PKCε) is upstream of and directly modulates the Rho GTPase signaling cascade, RhoA and RhoC, to control cell invasion and motility [7]
A prospective study showed that elevated PKCε in the primary tumor of HNSCC patients is associated with an increase in disease recurrence and a decrease in overall survival [8]
Summary
Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent cancer worldwide. We determined the effects of a novel cancer cell homing, PKCε inhibitory peptide on HNSCC cells in vitro and in vivo. To determine the efficiency and selectivity of HN1-PKCε for HNSCC cells in vitro, oral epithelial cells (NOE), UMSCC1, and UMSCC36 were untreated or treated with a series of different fluorescein isothiocyanate (FITC)-labeled peptides (3 μM for 48 hours), followed by fluorescence-activated cell sorting (FACS) analysis (Figure 1A).
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