aPKClambda/iota promotes growth of prostate cancer cells in an autocrine manner through transcriptional activation of interleukin-6.

Understanding the mechanism by which hormone refractory prostate cancer (HRPC) develops remains a major issue. Alterations in HRPC include androgen receptor (AR) changes. In addition, the AR is activated by cytokines such as interleukin-6 (IL-6). Atypical protein kinase C (aPKClambda/iota) has been implicated in the progression of several cancers. Herein, we provide evidence that aPKClambda/iota expression correlates with prostate cancer recurrence. Experiments in vitro and in vivo revealed aPKClambda/iota to be involved in prostate cancer cell growth through secretion of IL-6. Further, aPKClambda/iota activates transcription of the IL-6 gene through NFkappaB and AP-1. We conclude that aPKClambda/iota promotes the growth of hormone independent prostate cancer cells by stimulating IL-6 production in an autocrine manner. Our findings not only explain the link between aPKClambda/iota and IL-6, implicated in the progression a variety of cancers, but also establish a molecular change involved in the development of HRPC. Further, aPKClambda/iota expression might be a biomarker for prostate cancer progression.

Antitumor and antiangiogenic effects of interleukin 12 gene therapy in murine head and neck carcinoma model.

Interleukin-12 (IL-12) plays a critical role in producing an immune response, as indicated in many ways, e.g., induction of interferon-gamma (IFN-gamma), and augmentation of the cytotoxic activity of resting activated T cells and natural killer (NK) cells. In this study, we examined whether intratumoral injection of a recombinant retrovirus vector expressing IL-12s induce antitumor and antiangiogenic effects in a murine model using a murine head and neck squamous cell carcinoma (NR-S1). In vitro the levels of vascular endothelial growth factor (VEGF) mRNA and protein expression were decreased in IL-12 gene transfected NR-S1 cell. in vivo direct IL-12 gene therapy resulted in significantly remarkable inhibition of tumor growth compared to the control group. The tumor regression by direct IL-12 gene therapy was also associated with decreased vessel density, and apoptosis and increased infiltration of CD8(+) T cells and CD56(+) NK cells in the tumor increased. Also, the number of IFN-gamma expressed cells of spleen cells was increased in the treatment group compared with the control group. These results suggested that direct IL-12 gene therapy appears to be effective in reducing tumor growth by triggering both antiangiogenic effects and an immunological enhancing mechanism through induction of IFN-gamma.

The relationship of the human glutathione S-transferase P1 polymorphism and chemotherapeutic sensitivity in head and neck squamous carcinoma.

GSTP1, which encodes GSTPi, has a polymorphic site at codon 105 (exon 5), where an adenosine-to-guanine (A-G) transition causes an isoleucine-to-valine substitution (I105V). Recent studies have found that subjects with the valine allele display a significantly lower enzyme activity and less effective capability of detoxification. We hypothesized that head and neck squamous cell carcinoma (HNSCC) might respond differently to chemotherapeutic agents, especially cisplatin (CDDP) because of the presence of GSTP1 I105V polymorphism. Seventeen types of HNSCC cell lines were investigated with the MTT method, western blot, RT-PCR and direct sequence to examine the relationship between the sensitivity to CDDP and expression of GSTPi. There was a significant degree of difference in cell death among each cell line in the sensitivity test with CDDP, however, we did not find differences in the band density of the protein and mRNA expression levels of GSTPi. In the direct sequence examination we detected 4 subjects heterozygous of polymorphism GSTP1. The frequency was 23.5% in the 17 cell lines examined, and all 4 subjects showed a good response to CDDP treatment. A heterozygous polymorphism might alter the function of the GSTPi due to significantly lower enzyme activity and less effective capability of detoxification. Two other subjects which showed a good response to CDDP treatment did not show any polymorphism. These results indicated that there is another locus that reduces GSTPi activity, and that the mechanisms of CDDP resistance was multifactorial. Further study is required to conclude whether the GSTP1 I105V polymorphism might be useful as a predictive marker for multi-drug resistance.

Anti-tumor effect of vitamin A and D on head and neck squamous cell carcinoma.

OBJECTIVES: Vitamin A and D(3) have a very strong differentiation induction effect. STUDY DESIGN: We examined the anti tumor effect on head and neck squamous cell carcinoma (HNSCC) by treatment with several vitamins having strong differentiation induction effects in vitro. METHODS: We used KB cell that an oral floor squamous cell carcinoma, vitamins as all-trans retinoic acid (ATRA), 4-[3,5-bis (trimethylsilyl) benzamido] benzoic acid (TAC-101), 1alpha,25(OH)(2)D(3) (calcitriol) and 22-oxa-1,25-(OH)(2)D(3) (OCT). We determined receptors of vitamin A and D(3) using RT-PCR. Furthermore, we investigated the proliferation of tumor cells in concentration dependency using [3H]TdR uptake method, apoptosis and apoptosis related factors using TUNEL method and real-time PCR, cell cycle changes using flow cytometry, changing of the sensitivity of using MTT method, cytokine production and the angiogenesis factor using ELISA, by treatment with these vitamins. RESULTS: The deficit of RAR-beta was found in the KB cell. Each vitamin suppressed the cell proliferation, induced apoptosis, and cell cycle arrest, upregulated sensitivity of the chemotherapeutics drugs and downregulated several angiogenesis factors and an apoptotic factor; survivin. CONCLUSIONS: These results support the idea that vitamin A, D(3) and their derivatives are useful for preventing and/or treating patients with HNSCC.

Reduction of in vivo tumor growth by MMI-166, a selective matrix metalloproteinase inhibitor, through inhibition of tumor angiogenesis in squamous cell carcinoma cell lines of head and neck.

Matrix metalloproteinases (MMPs) have been implicated in tumor invasion, metastasis, and angiogenesis. We have recently shown that MMI-166, a new orally active MMP inhibitor specific for MMP-2 and -9, suppressed experimental metastasis of Lewis lung cancer, C-H1 human colon cancer, and pancreatic cancer without affecting tumor growth in vitro. In the present study, we determined whether oral administration of MMI-166 reduces tumor growth not only in such tumors but also in squamous cell carcinoma of head and neck (SCCHN). MMI-166 inhibited both activity of MMP-2 and -9 without affecting steady state levels of their mRNAs in SCCHN. Interestingly, protein levels of MMP-2 and -9 from the cultures were drastically diminished by culturing with MMI-166. This was also observed in xenografts of MMI-166-administered mice. In addition, daily oral administration of MMI-166 (100mg/kg) inhibited local tumor growth accompanied by the reduction of blood vessel density and Ki-67-positivity and increase in terminal deoxynucleotidyl transferase-mediated cUDP nick-end labeling (TUNEL)-positivity. These results suggested that orally administered MMI-166 reduced in vivo tumor growth of SCCHN through inhibition of angiogenesis and induction of apoptosis accompanied by the reduction of MMP productions and activities. Therefore, MMI-166 seems to be useful for tumor dormancy therapy of SCCHN.