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Multi-Leu PACE4 Inhibitor Retention within Cells Is PACE4 Dependent and a Prerequisite for Antiproliferative Activity.

Couture F, Ly K, Levesque C, Kwiatkowska A, Ait-Mohand S, Desjardins R, Guérin B, Day R - Biomed Res Int (2015)

Bottom Line: The overexpression as well as the critical implication of the proprotein convertase PACE4 in prostate cancer progression has been previously reported and supported the development of peptide inhibitors.The multi-Leu peptide, a PACE4-specific inhibitor, was further generated and its capability to be uptaken by tumor xenograft was demonstrated with regard to its PACE4 expression status.PACE4-knockdown associated growth deficiencies were established on the knockdown HepG2, Huh7, and HT1080 cells as well as the antiproliferative effects of the multi-Leu peptide supporting the growth capabilities of PACE4 in cancer cells.

View Article: PubMed Central - PubMed

Affiliation: Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, Canada J1H 5N4 ; Department of Surgery/Urology Division, Université de Sherbrooke, Sherbrooke, QC, Canada J1H 5N4.

ABSTRACT
The overexpression as well as the critical implication of the proprotein convertase PACE4 in prostate cancer progression has been previously reported and supported the development of peptide inhibitors. The multi-Leu peptide, a PACE4-specific inhibitor, was further generated and its capability to be uptaken by tumor xenograft was demonstrated with regard to its PACE4 expression status. To investigate whether the uptake of this inhibitor was directly dependent of PACE4 levels, uptake and efflux from cancer cells were evaluated and correlations were established with PACE4 contents on both wild type and PACE4-knockdown cell lines. PACE4-knockdown associated growth deficiencies were established on the knockdown HepG2, Huh7, and HT1080 cells as well as the antiproliferative effects of the multi-Leu peptide supporting the growth capabilities of PACE4 in cancer cells.

No MeSH data available.


Related in: MedlinePlus

PACE4 expression levels in the studied cell lines. Quantitative PCR (qPCR) measurement of PACE4 expression levels in both control and PACE4-knockdown cell lines. Data are means ± SEM of mRNA levels from at least 3 independent cell cultures using β-actin as the reference housekeeping gene.
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fig1: PACE4 expression levels in the studied cell lines. Quantitative PCR (qPCR) measurement of PACE4 expression levels in both control and PACE4-knockdown cell lines. Data are means ± SEM of mRNA levels from at least 3 independent cell cultures using β-actin as the reference housekeeping gene.

Mentions: To address the relation between 64Cu/NOTA-ML cell uptake and PACE4 status, an array of cell lines was screened for their endogenous expression levels of PACE4 by qPCR. Among prostate cancer cells, LNCaP cells have previously been reported to have higher levels of PACE4 than DU145 cells, whereas PC3 cells are PACE4-negative [11]. To further increase the range of PACE4 expressing cells, HepG2 and Huh7 hepatocellular carcinoma cell lines as well as HT1080 fibrosarcoma cells were assayed for their relative PACE4 mRNA levels (Figure 1). All these cells expressed PACE4 at variable levels, for example, HepG2 having the highest levels, directly followed by Huh7 and finally by HT1080, which had levels close to LNCaP cells. HepG2 cells were previously reported to express considerably high PACE4 levels [17], just like liver cells [18] and HT1080 were also known to express PACE4 [19]. To provide an appropriate control for each of these cell lines, a stable PACE4-knockdown cell line was generated for each of these PACE4-expressing cell lines using lentiviral transduction of PACE4-targeting shRNA. In each case, stable transduction yielded at least a 70% reduction of PACE4 expression in knockdown cells when compared to its respective controls (Figure 1), thus providing an even larger array of PACE4 expression levels.


Multi-Leu PACE4 Inhibitor Retention within Cells Is PACE4 Dependent and a Prerequisite for Antiproliferative Activity.

Couture F, Ly K, Levesque C, Kwiatkowska A, Ait-Mohand S, Desjardins R, Guérin B, Day R - Biomed Res Int (2015)

PACE4 expression levels in the studied cell lines. Quantitative PCR (qPCR) measurement of PACE4 expression levels in both control and PACE4-knockdown cell lines. Data are means ± SEM of mRNA levels from at least 3 independent cell cultures using β-actin as the reference housekeeping gene.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4465654&req=5

fig1: PACE4 expression levels in the studied cell lines. Quantitative PCR (qPCR) measurement of PACE4 expression levels in both control and PACE4-knockdown cell lines. Data are means ± SEM of mRNA levels from at least 3 independent cell cultures using β-actin as the reference housekeeping gene.
Mentions: To address the relation between 64Cu/NOTA-ML cell uptake and PACE4 status, an array of cell lines was screened for their endogenous expression levels of PACE4 by qPCR. Among prostate cancer cells, LNCaP cells have previously been reported to have higher levels of PACE4 than DU145 cells, whereas PC3 cells are PACE4-negative [11]. To further increase the range of PACE4 expressing cells, HepG2 and Huh7 hepatocellular carcinoma cell lines as well as HT1080 fibrosarcoma cells were assayed for their relative PACE4 mRNA levels (Figure 1). All these cells expressed PACE4 at variable levels, for example, HepG2 having the highest levels, directly followed by Huh7 and finally by HT1080, which had levels close to LNCaP cells. HepG2 cells were previously reported to express considerably high PACE4 levels [17], just like liver cells [18] and HT1080 were also known to express PACE4 [19]. To provide an appropriate control for each of these cell lines, a stable PACE4-knockdown cell line was generated for each of these PACE4-expressing cell lines using lentiviral transduction of PACE4-targeting shRNA. In each case, stable transduction yielded at least a 70% reduction of PACE4 expression in knockdown cells when compared to its respective controls (Figure 1), thus providing an even larger array of PACE4 expression levels.

Bottom Line: The overexpression as well as the critical implication of the proprotein convertase PACE4 in prostate cancer progression has been previously reported and supported the development of peptide inhibitors.The multi-Leu peptide, a PACE4-specific inhibitor, was further generated and its capability to be uptaken by tumor xenograft was demonstrated with regard to its PACE4 expression status.PACE4-knockdown associated growth deficiencies were established on the knockdown HepG2, Huh7, and HT1080 cells as well as the antiproliferative effects of the multi-Leu peptide supporting the growth capabilities of PACE4 in cancer cells.

View Article: PubMed Central - PubMed

Affiliation: Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, Canada J1H 5N4 ; Department of Surgery/Urology Division, Université de Sherbrooke, Sherbrooke, QC, Canada J1H 5N4.

ABSTRACT
The overexpression as well as the critical implication of the proprotein convertase PACE4 in prostate cancer progression has been previously reported and supported the development of peptide inhibitors. The multi-Leu peptide, a PACE4-specific inhibitor, was further generated and its capability to be uptaken by tumor xenograft was demonstrated with regard to its PACE4 expression status. To investigate whether the uptake of this inhibitor was directly dependent of PACE4 levels, uptake and efflux from cancer cells were evaluated and correlations were established with PACE4 contents on both wild type and PACE4-knockdown cell lines. PACE4-knockdown associated growth deficiencies were established on the knockdown HepG2, Huh7, and HT1080 cells as well as the antiproliferative effects of the multi-Leu peptide supporting the growth capabilities of PACE4 in cancer cells.

No MeSH data available.


Related in: MedlinePlus