We examined whether survivin acts as a constitutive and inducible radioresistance factor in pancreatic cancer cells. Using a quantitative TaqMan reverse transcription-polymerase chain reaction for survivin mRNA in five pancreatic cancer cell lines, we found an inverse relationship between survivin mRNA expression and radiosensitivity. PANC-1 cells, which had the highest survivin mRNA levels, were most resistant to X-irradiation; MIAPaCa-2 cells, which showed the least survivin mRNA expression, were the most sensitive to X-irradiation. Our results suggested that survivin could act as a constitutive radioresistance factor in pancreatic cancer cells. To determine whether radioresistance is enhanced by induction of survivin expression by irradiation, PANC-1 and MIAPaCa-2 cells were subjected to sublethal doses of X-irradiation followed by a lethal dose. Survivin mRNA expression was increased significantly in both PANC-1 and MIAPaCa-2 cell lines by pretreatment with a sublethal dose of X-irradiation, as was cell survival after exposure to the lethal dose. In this system, enzymatic caspase-3 activity was significantly suppressed in cells with acquired resistance. These results suggest that survivin also acts as an inducible radioresistance factor in pancreatic cancer cells. Survivin, then, appears to enhance radioresistance in pancreatic cancer cells; inhibition of survivin mRNA expression may improve the effectiveness of radiotherapy.

Induction of olfactomedin 4 (OLFM4GW112

Overexpression of the olfactomedin 4 (OLFM4GW112) gene was recently reported to inhibit various apoptotic pathways and promote proliferation of cancer cells, suggesting that OLFM4 might serve as a diagnostic marker for human cancers. Therefore, we examined cancer-specific OLFM4 overexpression. OLFM4 mRNA was highly expressed in cancerous tissues obtained from the colon, breast and lung. Positivity for OLFM4 mRNA, defined as the mean + + + + 2 SD in non-cancerous colon and breast tissues, was observed in 68 and 50% of the studied colon and breast cancer tissues. OLFM4 mRNA expression was not detected in non-cancerous lung tissues but was evident in 62% of the lung cancer tissues. On comparing paired samples, the expression of OLFM4 mRNA was observed to be elevated in 90, 69 and 85% of colon, breast and lung cancer tissues, respectively. OLFM4 mRNA expression was observed even in the early stages of each cancer type. The expression of OLFM4 mRNA did not correlate with that of the antiapoptotic molecule survivin, indicating that it can be used independently in cancer diagnosis. Combining OLFM4 and survivin resulted in higher positivity. Thus, OLFM4 mRNA might be a useful tool to support the diagnosis of cancer, irrespective of the clinical stages. (Cancer Sci 2007; 98: 315-320)

Tamoxifen has been the mainstay of endocrine therapy for estrogen receptor-positive breast cancer. However, approximately 40% of breast cancer patients do not respond to tamoxifen treatment. Further, most tumors eventually acquire tamoxifen resistance. Therefore, it is necessary to develop effective modalities to enhance the efficacy of tamoxifen in breast cancer treatment. In this study, we investigated the mechanism by which breast cancer cells develop resistance against tamoxifen from the viewpoint of tamoxifen-induced apoptosis. Overexpression of the anti-apoptotic molecule survivin rendered the human breast cancer cells MCF-7 resistant to tamoxifen-induced apoptosis. To examine whether the down-regulation of survivin can enhance tamoxifen-induced apoptosis, we introduced siRNA targeting the survivin gene (survivin-siRNA) into MCF-7 cells. Survivin-siRNA transfection not only induced apoptosis without tamoxifen treatment but also augmented the tamoxifen-induced apoptosis. We have previously demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HRIs), which are widely used to reduce the serum cholesterol levels in hypercholesterolemia patients, decreases survivin expression in colon cancer cells. To develop a pharmacological approach for improving the efficacy of tamoxifen treatment, we determined whether HRIs can enhance tamoxifen-induced apoptosis. Lovastatin, an HRI, down-regulated the expression of survivin protein in MCF-7 cells in a dose-dependent manner. In addition, the proportion of apoptotic cells induced by the tamoxifen and lovastatin combination was greater than the theoretical additive effect. These results suggest that survivin may function as a factor inducing resistance against tamoxifen-induced apoptosis, and the combined use of tamoxifen and HRI may be a novel approach to overcome tamoxifen resistance in breast cancer.

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