scholarly journals Insulin-like Growth Factor-1 Influences Prostate Cancer Cell Growth and Invasion through an Integrin α3, α5, αV, and β1 Dependent Mechanism

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 363
Author(s):  
Carolin Siech ◽  
Jochen Rutz ◽  
Sebastian Maxeiner ◽  
Timothy Grein ◽  
Marlon Sonnenburg ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Growth Factor ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Mtor Signaling ◽  
Insulin Like Growth Factor ◽  
Cancer Cell Growth ◽  
Knock Down ◽  
Pc3 Cells ◽  
Du145 Cells

Insulin-like growth factor-1 (IGF-1)-related signaling is associated with prostate cancer progression. Links were explored between IGF-1 and expression of integrin adhesion receptors to evaluate relevance for growth and migration. Androgen-resistant PC3 and DU145 and androgen-sensitive LNCaP and VCaP prostate cancer cells were stimulated with IGF-1 and tumor growth (all cell lines), adhesion and chemotaxis (PC3, DU145) were determined. Evaluation of Akt/mTOR-related proteins, focal adhesion kinase (FAK) and integrin α and β subtype expression followed. Akt knock-down was used to investigate its influence on integrin expression, while FAK blockade served to evaluate its influence on mTOR signaling. Integrin knock-down served to investigate its influence on tumor growth and chemotaxis. Stimulation with IGF-1 activated growth in PC3, DU145, and VCaP cells, and altered adhesion and chemotactic properties of DU145 and PC3 cells. This was associated with time-dependent alterations of the integrins α3, α5, αV, and β1, FAK phosphorylation and Akt/mTOR signaling. Integrin blockade or integrin knock-down in DU145 and PC3 cells altered tumor growth, adhesion, and chemotaxis. Akt knock-down (DU145 cells) cancelled the effect of IGF-1 on α3, α5, and αV integrins, whereas FAK blockade cancelled the effect of IGF-1 on mTOR signaling (DU145 cells). Prostate cancer growth and invasion are thus controlled by a fine-tuned network between IGF-1 driven integrin-FAK signaling and the Akt-mTOR pathway. Concerted targeting of integrin subtypes along with Akt-mTOR signaling could, therefore, open options to prevent progressive dissemination of prostate cancer.

Effect of inhibition of Src and insulin/insulin-like growth factor-1 receptor (IR/IGF-1R) on tumor activity and bone turnover in prostate cancer (PCa) models in vivo relative to inhibition of either kinase alone.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15151-e15151
Author(s):  
Farshid Dayyani ◽  
John C. Araujo ◽  
Joan M. Carboni ◽  
Marco M. Gottardis ◽  
Geralyn Carol Trudel ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Growth Factor ◽  
Bone Turnover ◽  
Tumor Growth ◽  
Insulin Like Growth Factor ◽  
Antitumor Effects ◽  
Western Blots ◽  
Pc3 Cells

e15151 Background: Growth of prostate cancer (PCa) metastases relies on bidirectional interactions between the tumor and microenvironment.The Src family kinases (SFK) and insulin-like growth factor-1 receptor (IGF-1R) signaling axes are aberrantly activated in both PCa and the microenvironment of bone metastases. Dasatinib and BMS-754807 are small molecule inhibitors that target SFK and IGF-1R/IR, respectively. This study examined the in vitro and in vivo effects of BMS-754807 and dasatinib on PCa growth. Methods: Antitumor effects of both reagents were tested alone and in combination in vitro in PC3 and LNCaP cells, using proliferation and apoptosis assays. Signaling pathways were interrogated by western blots. Tumor growth in vivo was assessed by orthotopic and intratibial injection of PC3 cells and subcutaneous growth of primary human xenograft PCa-133b. Serum markers were measured by ELISA. Results: In vitro, dasatinib decreased proliferation and migration of PCa cells whereas BMS-754807 induced apoptosis. All observed anti-tumor effects were enhanced when dual blockade was used. IGF-1 induced phosphorylation of Akt1, but not Akt2, was partially inhibited by either drug alone and almost completely abrogated by the combination. Dasatinib and BMS-754807 inhibited in vivo orthotopic and intratibial tumor growth of PC3 cells more potently than either as a single agent alone with a corresponding decrease in bone turnover markers. Both drugs also exhibited synergism in primary human xenograft tumors. Potent target inhibition (p-Src, p-IGF-1R, p-Akt) by the drug combination was also demonstrated in xenografts. Conclusions: The combination of dasatinib and BMS-754807 may be a rational therapeutic approach in PCa by blocking both independent and complementary processes critical to tumor growth.

scholarly journals MAZ51 Blocks the Tumor Growth of Prostate Cancer by Inhibiting Vascular Endothelial Growth Factor Receptor 3

2021 ◽  
Vol 12 ◽  
Author(s):  
Aya Yamamura ◽  
Md Junayed Nayeem ◽  
Hiroyuki Muramatsu ◽  
Kogenta Nakamura ◽  
Motohiko Sato
Keyword(s):  
Prostate Cancer ◽  
Vascular Endothelial Growth Factor ◽  
Cell Proliferation ◽  
Growth Factor ◽  
Tumor Growth ◽  
Metastatic Prostate Cancer ◽  
Vascular Endothelial ◽  
Du145 Cells ◽  
Endothelial Growth Factor ◽  
Androgen Independent

Vascular endothelial growth factor (VEGF) signaling plays a critical role in the carcinogenesis and tumor development of several cancer types. However, its pathological significance in prostate cancer, one of the most frequent and lethal malignancies in men, remains unclear. In the present study, we focused on a pathological role of the VEGF receptors (VEGFRs), and examined their expression and effects of MAZ51 (an inhibitor of the tyrosine kinase of VEGFR-3) on cell proliferation, migration, and tumor growth in human prostate cancer cells. The expression level of VEGFR-3 was higher in androgen-independent and highly metastatic prostate cancer PC-3 cells than in other prostate PrEC, LNCaP, and DU145 cells. In PC-3 cells, VEGFR-3 and Akt were phosphorylated following a stimulation with 50 ng/ml VEGF-C, and these phosphorylations were blocked by 3 μM MAZ51. Interestingly, PC-3 cells themselves secreted VEGF-C, which was markedly larger amount compared with PrEC, LNCaP, and DU145 cells. MAZ51 reduced the expression of VEGFR-3 but not VEGFR-1 and VEGFR-2. The proliferation of PC-3 cells was inhibited by MAZ51 (IC50 = 2.7 μM) and VEGFR-3 siRNA, and partly decreased by 100 nM GSK690693 (an Akt inhibitor) and 300 nM VEGFR2 Kinase Inhibitor I. MAZ51 and VEGFR-3 siRNA also attenuated the VEGF-C-induced migration of PC-3 cells. Moreover, MAZ51 blocked the tumor growth of PC-3 cells in a xenograft mouse model. These results suggest that VEGFR-3 signaling contributes to the cell proliferation, migration, and tumor growth of androgen-independent/highly metastatic prostate cancer. Therefore, the inhibition of VEGFR-3 has potential as a novel therapeutic target for the treatment for prostate cancer.

scholarly journals Growth, Proliferation and Metastasis of Prostate Cancer Cells Is Blocked by Low-Dose Curcumin in Combination with Light Irradiation

2021 ◽  
Vol 22 (18) ◽  
pp. 9966
Author(s):  
Jochen Rutz ◽  
Aicha Benchellal ◽  
Wajdi Kassabra ◽  
Sebastian Maxeiner ◽  
August Bernd ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Growth ◽  
Tumor Growth ◽  
Visible Light ◽  
Light Irradiation ◽  
Cancer Cell Growth ◽  
Proliferation And Metastasis ◽  
Pc3 Cells ◽  
And Migration

Although anti-cancer properties of the natural compound curcumin have been reported, low absorption and rapid metabolisation limit clinical use. The present study investigated whether irradiation with visible light may enhance the inhibitory effects of low-dosed curcumin on prostate cancer cell growth, proliferation, and metastasis in vitro. DU145 and PC3 cells were incubated with low-dosed curcumin (0.1–0.4 µg/mL) and subsequently irradiated with 1.65 J/cm2 visible light for 5 min. Controls remained untreated and/or non-irradiated. Cell growth, proliferation, apoptosis, adhesion, and chemotaxis were evaluated, as was cell cycle regulating protein expression (CDK, Cyclins), and integrins of the α- and β-family. Curcumin or light alone did not cause any significant effects on tumor growth, proliferation, or metastasis. However, curcumin combined with light irradiation significantly suppressed tumor growth, adhesion, and migration. Phosphorylation of CDK1 decreased and expression of the counter-receptors cyclin A and B was diminished. Integrin α and β subtypes were also reduced, compared to controls. Irradiation distinctly enhances the anti-tumor potential of curcumin in vitro and may hold promise in treating prostate cancer.

scholarly journals Cytostatic Action of Novel Histone Deacetylase Inhibitors in Androgen Receptor-Null Prostate Cancer Cells

2021 ◽  
Vol 14 (2) ◽  
pp. 103
Author(s):  
Zohaib Rana ◽  
Joel D. A. Tyndall ◽  
Muhammad Hanif ◽  
Christian G. Hartinger ◽  
Rhonda J. Rosengren
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Hdac Inhibitors ◽  
G1 Arrest ◽  
Prostate Cancer Cells ◽  
Prostate Tumors ◽  
Normal Prostate ◽  
Pc3 Cells ◽  
Du145 Cells

Androgen receptor (AR)-null prostate tumors have been observed in 11–24% of patients. Histone deacetylases (HDACs) are overexpressed in prostate tumors. Therefore, HDAC inhibitors (Jazz90 and Jazz167) were examined in AR-null prostate cancer cell lines (PC3 and DU145). Both Jazz90 and Jazz167 inhibited the growth of PC3 and DU145 cells. Jazz90 and Jazz167 were more active in PC3 cells and DU145 cells in comparison to normal prostate cells (PNT1A) and showed a 2.45- and 1.30-fold selectivity and higher cytotoxicity toward DU145 cells, respectively. Jazz90 and Jazz167 reduced HDAC activity by ~60% at 50 nM in PC3 lysates. At 4 μM, Jazz90 and Jazz167 increased acetylation in PC3 cells by 6- to 8-fold. Flow cytometry studies on the cell phase distribution demonstrated that Jazz90 causes a G0/G1 arrest in AR-null cells, whereas Jazz167 leads to a G0/G1 arrest in DU145 cells. However, apoptosis only occurred at a maximum of 7% of the total cell population following compound treatments in PC3 and DU145 cells. There was a reduction in cyclin D1 and no significant changes in bcl-2 in DU145 and PC3 cells. Overall, the results showed that Jazz90 and Jazz167 function as cytostatic HDAC inhibitors in AR-null prostate cancer cells.

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