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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

Forced restoration of prostasin represses and re-sensitizes chemoresistant tumors. (a) Overexpression of prostasin represses and re-sensitizes chemoresistant tumors. O432-RP-pro-O cells (stably transfected with prostasin cDNA) or control cells O432-RP-C (stably transfected with control pCI-neo vector) were injected into the left and right flanks of mice, respectively. The animals were treated with paclitaxel (15 mg/kg/week) or control vehicle PBS for 2 weeks after the tumors reached about 100 or 50 mm3. Tumor volumes before and after treatment are shown. O432-RP-psp-O-c and O432-RP-psp-O-t: PBS- and paclitaxel-treated O432-RP-psp-O tumors; O432-RP-C-c and O432-RP-C-t: PBS- and paclitaxel-treated O432-RP-C tumors. n=6 per group, **P<0.01. Mean±s.d. are given, and the P-values were calculated using the two-sided Student's t-test. (b) Tumors in mice before and after treatments. Scale bar=5 mm
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fig3: Forced restoration of prostasin represses and re-sensitizes chemoresistant tumors. (a) Overexpression of prostasin represses and re-sensitizes chemoresistant tumors. O432-RP-pro-O cells (stably transfected with prostasin cDNA) or control cells O432-RP-C (stably transfected with control pCI-neo vector) were injected into the left and right flanks of mice, respectively. The animals were treated with paclitaxel (15 mg/kg/week) or control vehicle PBS for 2 weeks after the tumors reached about 100 or 50 mm3. Tumor volumes before and after treatment are shown. O432-RP-psp-O-c and O432-RP-psp-O-t: PBS- and paclitaxel-treated O432-RP-psp-O tumors; O432-RP-C-c and O432-RP-C-t: PBS- and paclitaxel-treated O432-RP-C tumors. n=6 per group, **P<0.01. Mean±s.d. are given, and the P-values were calculated using the two-sided Student's t-test. (b) Tumors in mice before and after treatments. Scale bar=5 mm

Mentions: We extended our in vitro finding to a mouse tumor model to explore the potential of prostasin as a therapeutic target for treating/repressing some ovarian tumors. The tumor cells of O432-RP-pro-O and O432-RP-C were implanted into each flank of mice. These tumor-bearing animals were treated with paclitaxel or vehicle PBS when the tumor volume reaches about 100 mm3 (the tumor volume of O432-RP-C is about 100 mm3at the time of treatment; however, the volume of O432-RP-pro-O tumor is only about 50 mm3 because of low growth rate of cells). At the end of treatment, we compared the tumor volumes of O432-RP-C and O432-RP-pro-O in the presence and absence of paclitaxel, respectively. In the absence of paclitaxel treatment (e.g., just vehicle PBS), we observed that O432-RP-pro-O tumors were significantly smaller compared with that of O432-RP-C control tumors (P<0.01, Figures 3a and b). We believe this is probably due to the low growth rate of this cell line, which overexpressed prostasin. In addition, we observed that the O432-RP-pro-O tumors became further smaller when treated with paclitaxel (P<0.001, Figures 3a and b), and paclitaxel-treated O432-RP-pro-O tumors were slightly smaller than PBS-treated O432-RP-pro-O tumors (P<0.1, Figures 3a and b). The data suggest that restoration of prostasin in chemoresistant cells inhibits growth of these tumors and may partially reverse chemoresistance, which is consistent with our in vitro findings.


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)

Forced restoration of prostasin represses and re-sensitizes chemoresistant tumors. (a) Overexpression of prostasin represses and re-sensitizes chemoresistant tumors. O432-RP-pro-O cells (stably transfected with prostasin cDNA) or control cells O432-RP-C (stably transfected with control pCI-neo vector) were injected into the left and right flanks of mice, respectively. The animals were treated with paclitaxel (15 mg/kg/week) or control vehicle PBS for 2 weeks after the tumors reached about 100 or 50 mm3. Tumor volumes before and after treatment are shown. O432-RP-psp-O-c and O432-RP-psp-O-t: PBS- and paclitaxel-treated O432-RP-psp-O tumors; O432-RP-C-c and O432-RP-C-t: PBS- and paclitaxel-treated O432-RP-C tumors. n=6 per group, **P<0.01. Mean±s.d. are given, and the P-values were calculated using the two-sided Student's t-test. (b) Tumors in mice before and after treatments. Scale bar=5 mm
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Forced restoration of prostasin represses and re-sensitizes chemoresistant tumors. (a) Overexpression of prostasin represses and re-sensitizes chemoresistant tumors. O432-RP-pro-O cells (stably transfected with prostasin cDNA) or control cells O432-RP-C (stably transfected with control pCI-neo vector) were injected into the left and right flanks of mice, respectively. The animals were treated with paclitaxel (15 mg/kg/week) or control vehicle PBS for 2 weeks after the tumors reached about 100 or 50 mm3. Tumor volumes before and after treatment are shown. O432-RP-psp-O-c and O432-RP-psp-O-t: PBS- and paclitaxel-treated O432-RP-psp-O tumors; O432-RP-C-c and O432-RP-C-t: PBS- and paclitaxel-treated O432-RP-C tumors. n=6 per group, **P<0.01. Mean±s.d. are given, and the P-values were calculated using the two-sided Student's t-test. (b) Tumors in mice before and after treatments. Scale bar=5 mm
Mentions: We extended our in vitro finding to a mouse tumor model to explore the potential of prostasin as a therapeutic target for treating/repressing some ovarian tumors. The tumor cells of O432-RP-pro-O and O432-RP-C were implanted into each flank of mice. These tumor-bearing animals were treated with paclitaxel or vehicle PBS when the tumor volume reaches about 100 mm3 (the tumor volume of O432-RP-C is about 100 mm3at the time of treatment; however, the volume of O432-RP-pro-O tumor is only about 50 mm3 because of low growth rate of cells). At the end of treatment, we compared the tumor volumes of O432-RP-C and O432-RP-pro-O in the presence and absence of paclitaxel, respectively. In the absence of paclitaxel treatment (e.g., just vehicle PBS), we observed that O432-RP-pro-O tumors were significantly smaller compared with that of O432-RP-C control tumors (P<0.01, Figures 3a and b). We believe this is probably due to the low growth rate of this cell line, which overexpressed prostasin. In addition, we observed that the O432-RP-pro-O tumors became further smaller when treated with paclitaxel (P<0.001, Figures 3a and b), and paclitaxel-treated O432-RP-pro-O tumors were slightly smaller than PBS-treated O432-RP-pro-O tumors (P<0.1, Figures 3a and b). The data suggest that restoration of prostasin in chemoresistant cells inhibits growth of these tumors and may partially reverse chemoresistance, which is consistent with our in vitro findings.

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