Limits...
Prostasin may contribute to chemoresistance, repress cancer cells in ovarian cancer, and is involved in the signaling pathways of CASP/PAK2-p34/actin.

Yan BX, Ma JX, Zhang J, Guo Y, Mueller MD, Remick SC, Yu JJ - Cell Death Dis (2014)

Bottom Line: In this study, we show that prostasin is decreased in an ovarian cancer drug-resistant cell line and in ovarian cancer patients with high levels of excision repair cross-complementing 1, a marker for chemoresistance.In addition, the surviving cells grow at a much lower rate compared with non-overexpressed cells.Our investigation of the molecular mechanisms suggests that prostasin may repress cancer cells and/or contribute to chemoresistance by modulating the CASP/P21-activated protein kinase (PAK2)-p34 pathway, and thereafter PAK2-p34/JNK/c-jun and PAK2-p34/mlck/actin signaling pathways.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Biochemistry, School of Medicine, Department of Basic Pharmaceutical Sciences, School of Pharmacy, and Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV 26506, USA [2] IcesnowYanyan Bioscience Association, Beijing 00094, China.

ABSTRACT
Ovarian cancer is the deadliest of gynecologic cancers, largely due to the development of drug resistance in chemotherapy. Prostasin may have an essential role in the oncogenesis. In this study, we show that prostasin is decreased in an ovarian cancer drug-resistant cell line and in ovarian cancer patients with high levels of excision repair cross-complementing 1, a marker for chemoresistance. Our cell cultural model investigation demonstrates prostasin has important roles in the development of drug resistance and cancer cell survival. Forced overexpression of prostasin in ovarian cancer cells greatly induces cell death (resulting in 99% cell death in a drug-resistant cell line and 100% cell death in other tested cell lines). In addition, the surviving cells grow at a much lower rate compared with non-overexpressed cells. In vivo studies indicate that forced overexpression of prostasin in drug-resistant cells greatly inhibits the growth of tumors and may partially reverse drug resistance. Our investigation of the molecular mechanisms suggests that prostasin may repress cancer cells and/or contribute to chemoresistance by modulating the CASP/P21-activated protein kinase (PAK2)-p34 pathway, and thereafter PAK2-p34/JNK/c-jun and PAK2-p34/mlck/actin signaling pathways. Thus, we introduce prostain as a potential target for treating/repressing some ovarian tumors and have begun to identify their relevant molecular targets in specific signaling pathways.

Show MeSH

Related in: MedlinePlus

Reduced prostasin expression in patients with high expression of ERCC1, a marker for chemoresistance in ovarian cancer. (a) Prostasin mRNA levels were compared in tumors with high ERCC1 levels (ERCC1 average=1.54, n=18) representing the chemoresistant phenotype, and in tumors with low ERCC1 levels (ERCC1 average=0.44, n=31) representing the chemosensitive phenotype26, 27 by real-time qPCR analysis. Relative levels of prostasin in chemoresistant versus chemosensitive tumors are shown, respectively. **P<0.01. Mean±s.d. are given, and P values were calculated using the two-sided Student's t-test. (b) Expression of prostasin by fluorescent immunohistochemistry in (patient-derived) ovarian tumor samples. Prostasin is decreased in ovarian ERCC1-high tumors compared with the ERCC1-low tumors
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4043260&req=5

fig1: Reduced prostasin expression in patients with high expression of ERCC1, a marker for chemoresistance in ovarian cancer. (a) Prostasin mRNA levels were compared in tumors with high ERCC1 levels (ERCC1 average=1.54, n=18) representing the chemoresistant phenotype, and in tumors with low ERCC1 levels (ERCC1 average=0.44, n=31) representing the chemosensitive phenotype26, 27 by real-time qPCR analysis. Relative levels of prostasin in chemoresistant versus chemosensitive tumors are shown, respectively. **P<0.01. Mean±s.d. are given, and P values were calculated using the two-sided Student's t-test. (b) Expression of prostasin by fluorescent immunohistochemistry in (patient-derived) ovarian tumor samples. Prostasin is decreased in ovarian ERCC1-high tumors compared with the ERCC1-low tumors

Mentions: ERCC1, the essential nucleotide excision repair component, is a biomarker for chemoresistance and a target to overcome chemoresistance in cancer therapy.26, 27, 28, 29, 30 We proposed that prostasin may have role in chemoresistance because it is malexpressed in various types of cancers.8, 9, 10, 11 To investigate the possible association, we examined prostasin expression in ovarian tumor samples with known ERCC1 expression, representing chemoresistant phenotype.31 Real-time quantitative PCR data showed that prostasin expression was significantly lower in tumor samples from ERCC1-high group (n=18), compared with ERCC1-low group (n=31), and that prostasin mRNA is greatly reduced in potentially chemoresistant tumors compared with chemosensitive tumors (Figure 1a,P<0.01). We examined prostasin protein level in these tumor samples using immunohistochemistry. The data show that prostasin protein is decreased in chemoresistant/ERCC1-high tumors compared with chemosensitive/ERCC1-low tumors (Figure 1b), which is consistent with prostasin mRNA level. These results demonstrated that prostasin is decreased in ovarian tumors with high ERCC1 expression, the chemoresistant phenotype. Therefore, prostasin may have an important role in chemoresistance in ovarian cancer.


Prostasin may contribute to chemoresistance, repress cancer cells in ovarian cancer, and is involved in the signaling pathways of CASP/PAK2-p34/actin.

Yan BX, Ma JX, Zhang J, Guo Y, Mueller MD, Remick SC, Yu JJ - Cell Death Dis (2014)

Reduced prostasin expression in patients with high expression of ERCC1, a marker for chemoresistance in ovarian cancer. (a) Prostasin mRNA levels were compared in tumors with high ERCC1 levels (ERCC1 average=1.54, n=18) representing the chemoresistant phenotype, and in tumors with low ERCC1 levels (ERCC1 average=0.44, n=31) representing the chemosensitive phenotype26, 27 by real-time qPCR analysis. Relative levels of prostasin in chemoresistant versus chemosensitive tumors are shown, respectively. **P<0.01. Mean±s.d. are given, and P values were calculated using the two-sided Student's t-test. (b) Expression of prostasin by fluorescent immunohistochemistry in (patient-derived) ovarian tumor samples. Prostasin is decreased in ovarian ERCC1-high tumors compared with the ERCC1-low tumors
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4043260&req=5

fig1: Reduced prostasin expression in patients with high expression of ERCC1, a marker for chemoresistance in ovarian cancer. (a) Prostasin mRNA levels were compared in tumors with high ERCC1 levels (ERCC1 average=1.54, n=18) representing the chemoresistant phenotype, and in tumors with low ERCC1 levels (ERCC1 average=0.44, n=31) representing the chemosensitive phenotype26, 27 by real-time qPCR analysis. Relative levels of prostasin in chemoresistant versus chemosensitive tumors are shown, respectively. **P<0.01. Mean±s.d. are given, and P values were calculated using the two-sided Student's t-test. (b) Expression of prostasin by fluorescent immunohistochemistry in (patient-derived) ovarian tumor samples. Prostasin is decreased in ovarian ERCC1-high tumors compared with the ERCC1-low tumors
Mentions: ERCC1, the essential nucleotide excision repair component, is a biomarker for chemoresistance and a target to overcome chemoresistance in cancer therapy.26, 27, 28, 29, 30 We proposed that prostasin may have role in chemoresistance because it is malexpressed in various types of cancers.8, 9, 10, 11 To investigate the possible association, we examined prostasin expression in ovarian tumor samples with known ERCC1 expression, representing chemoresistant phenotype.31 Real-time quantitative PCR data showed that prostasin expression was significantly lower in tumor samples from ERCC1-high group (n=18), compared with ERCC1-low group (n=31), and that prostasin mRNA is greatly reduced in potentially chemoresistant tumors compared with chemosensitive tumors (Figure 1a,P<0.01). We examined prostasin protein level in these tumor samples using immunohistochemistry. The data show that prostasin protein is decreased in chemoresistant/ERCC1-high tumors compared with chemosensitive/ERCC1-low tumors (Figure 1b), which is consistent with prostasin mRNA level. These results demonstrated that prostasin is decreased in ovarian tumors with high ERCC1 expression, the chemoresistant phenotype. Therefore, prostasin may have an important role in chemoresistance in ovarian cancer.

Bottom Line: In this study, we show that prostasin is decreased in an ovarian cancer drug-resistant cell line and in ovarian cancer patients with high levels of excision repair cross-complementing 1, a marker for chemoresistance.In addition, the surviving cells grow at a much lower rate compared with non-overexpressed cells.Our investigation of the molecular mechanisms suggests that prostasin may repress cancer cells and/or contribute to chemoresistance by modulating the CASP/P21-activated protein kinase (PAK2)-p34 pathway, and thereafter PAK2-p34/JNK/c-jun and PAK2-p34/mlck/actin signaling pathways.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Biochemistry, School of Medicine, Department of Basic Pharmaceutical Sciences, School of Pharmacy, and Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV 26506, USA [2] IcesnowYanyan Bioscience Association, Beijing 00094, China.

ABSTRACT
Ovarian cancer is the deadliest of gynecologic cancers, largely due to the development of drug resistance in chemotherapy. Prostasin may have an essential role in the oncogenesis. In this study, we show that prostasin is decreased in an ovarian cancer drug-resistant cell line and in ovarian cancer patients with high levels of excision repair cross-complementing 1, a marker for chemoresistance. Our cell cultural model investigation demonstrates prostasin has important roles in the development of drug resistance and cancer cell survival. Forced overexpression of prostasin in ovarian cancer cells greatly induces cell death (resulting in 99% cell death in a drug-resistant cell line and 100% cell death in other tested cell lines). In addition, the surviving cells grow at a much lower rate compared with non-overexpressed cells. In vivo studies indicate that forced overexpression of prostasin in drug-resistant cells greatly inhibits the growth of tumors and may partially reverse drug resistance. Our investigation of the molecular mechanisms suggests that prostasin may repress cancer cells and/or contribute to chemoresistance by modulating the CASP/P21-activated protein kinase (PAK2)-p34 pathway, and thereafter PAK2-p34/JNK/c-jun and PAK2-p34/mlck/actin signaling pathways. Thus, we introduce prostain as a potential target for treating/repressing some ovarian tumors and have begun to identify their relevant molecular targets in specific signaling pathways.

Show MeSH
Related in: MedlinePlus