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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.

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Related in: MedlinePlus

Proposed model of prostasin-regulated signaling network affecting cell survival and/or chemoresistance. Prostasin appears to regulate cell survival and/or chemoresistance may be through CASPs/Pak2-p34 axis and thereafter PAK2-p34/JNK/c-jun and PAK2-p34/mlck/actin signaling pathways
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fig5: Proposed model of prostasin-regulated signaling network affecting cell survival and/or chemoresistance. Prostasin appears to regulate cell survival and/or chemoresistance may be through CASPs/Pak2-p34 axis and thereafter PAK2-p34/JNK/c-jun and PAK2-p34/mlck/actin signaling pathways

Mentions: To explore the upstream targets of PAK2-p34, we examined expression of several CASP genes, as PAK2-p34 is specifically cleaved by CASPs.34, 35 Interestingly, several CASPs were found increased in O432-RP-pro-O cells compared with O432-RP-C cells (Figures 4c and d). To confirm that PAK2-p34 is cleaved by CASPs, we blocked CASPs activity using CASPs inhibitors. We observed that the cleavage was blocked (PAK2-p34 decrease or disappear) as early as 12 h after incubating the cell with CASPs inhibitor (Figure 4e). Thus, CASPs are upstream targets of PAK2-p34 and downstream target of prostasin in our experimental system. We tried to identify the upstream signaling of CASPs in these cells, but were unsuccessful. We also checked the expression level of these prostasin downstream targets in prostasin knockdown cells O432-pro-D compared with the control, and a reverse pattern was revealed (Figure 4f). The data suggest that prostasin may affect chemoresistance and/or cell survival through regulating the CASPs/PAK2-p34 axis and thereafter JNK/c-jun and mlck/actin signaling pathways (Figure 5).


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)

Proposed model of prostasin-regulated signaling network affecting cell survival and/or chemoresistance. Prostasin appears to regulate cell survival and/or chemoresistance may be through CASPs/Pak2-p34 axis and thereafter PAK2-p34/JNK/c-jun and PAK2-p34/mlck/actin signaling pathways
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig5: Proposed model of prostasin-regulated signaling network affecting cell survival and/or chemoresistance. Prostasin appears to regulate cell survival and/or chemoresistance may be through CASPs/Pak2-p34 axis and thereafter PAK2-p34/JNK/c-jun and PAK2-p34/mlck/actin signaling pathways
Mentions: To explore the upstream targets of PAK2-p34, we examined expression of several CASP genes, as PAK2-p34 is specifically cleaved by CASPs.34, 35 Interestingly, several CASPs were found increased in O432-RP-pro-O cells compared with O432-RP-C cells (Figures 4c and d). To confirm that PAK2-p34 is cleaved by CASPs, we blocked CASPs activity using CASPs inhibitors. We observed that the cleavage was blocked (PAK2-p34 decrease or disappear) as early as 12 h after incubating the cell with CASPs inhibitor (Figure 4e). Thus, CASPs are upstream targets of PAK2-p34 and downstream target of prostasin in our experimental system. We tried to identify the upstream signaling of CASPs in these cells, but were unsuccessful. We also checked the expression level of these prostasin downstream targets in prostasin knockdown cells O432-pro-D compared with the control, and a reverse pattern was revealed (Figure 4f). The data suggest that prostasin may affect chemoresistance and/or cell survival through regulating the CASPs/PAK2-p34 axis and thereafter JNK/c-jun and mlck/actin signaling pathways (Figure 5).

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