Promote Apoptosis In Prostate Cancer Cells Research Articles

Dioscin Promotes Prostate Cancer Cell Apoptosis and Inhibits Cell Invasion by Increasing SHP1 Phosphorylation and Suppressing the Subsequent MAPK Signaling Pathway.

Dioscin possesses antioxidant effects and has anticancer ability in many solid tumors including prostate cancer (PCa). Nevertheless, its effect and mechanism of anti-PCa action remain unclear. The tyrosine protein phosphatase SHP1, which contains an oxidation-sensitive domain, has been confirmed as a target for multicancer treatment. Further studies are needed to determine whether dioscin inhibits PCa through SHP1. We performed in vitro studies using androgen-sensitive (LNCaP) and androgen-independent (LNCaP -C81) cells to investigate the anticancer effects and possible mechanisms of dioscin after administering interleukin-6 (IL-6) and dihydrotestosterone (DHT). Our results show that dioscin inhibited cell growth and invasion by increasing SHP1 phosphorylation [p-SHP1 (Y536)] and inhibiting the subsequent P38 mitogen-activated protein kinase signaling pathway. Further in vivo studies confirmed that dioscin promoted caspase-3 and Bad-related cell apoptosis in these two cell lines. Our research suggests that the anticancer effects of dioscin on PCa may occur through SHP1. Dioscin may be useful to treat androgen-sensitive and independent PCa in the future.

MiR-203 over-expression promotes prostate cancer cell apoptosis and reduces ADM resistance.

The article "MiR-203 over-expression promotes prostate cancer cell apoptosis and reduces ADM resistance, by Chen LZ, Ding Z, Zhang Y, He ST, Wang XH, published in Eur Rev Med Pharmacol Sci. 2018 Jun;22(12):3734-3741. DOI: 10.26355/eurrev_201806_15253. PMID: 29949147" has been withdrawn from the authors. The Publisher apologizes for any inconvenience this may cause.

Abstract 1992: Mesenchymal stem cell-derived interleukin-28 can drive the selection of apoptosis resistant bone metastatic prostate cancer

Abstract Bone metastatic prostate cancer is painful and incurable. We believe that understanding the interactions of tumor cells and the surrounding stromal cells may provide new therapeutic options. Bone metastatic prostate cancer promotes mesenchymal stem cell (MSC) recruitment and differentiation into osteoblasts, leading to the clinically often-observed osteogenic phenotype. However, the reciprocal roles of bone- marrow derived MSCs on prostate cancer cells are less explored. Here, we discovered that MSCs significantly suppress prostate cancer growth in vitro and in vivo. Mechanistically, we show that MSC-derived interleukin-28 (IL-28) promotes prostate cancer cell apoptosis via the IL-28 receptor alpha (IL-28Rα). However, chronic exposure to MSCs yields prostate cancer cell populations that are resistant to IL-28 induced apoptosis and therapeutics such as docetaxel. In vivo, we observed that MSC selected prostate cancer cells rather than being suppressed, grow at a significantly enhanced rate in bone. The increase in apoptosis resistance is accompanied by a shift in downstream signaling of the IL-28Rα from STAT1 to STAT3. Reduction of STAT3 levels or pharmacological inhibition (STI-201) significantly reduces the growth of MSC selected prostate cancer cells in vitro and in vivo. Collectively, these data shed light on how MSCs in the bone marrow microenvironment initially protect against prostate cancer cell establishment but in doing so, help select for aggressive, apoptosis resistant bone metastatic prostate cancer cells that are more aggressive. Given that the majority of prostate to bone metastases are positive for STAT3 expression and activity, our data provide rationale for the therapeutic targeting of STAT3 in bone metastatic prostate cancer. Citation Format: Jeremy J. Mcguire, Leah Cook, Jeremy Frieling, Ayaz Muhammad, Harshani Lawrence, Nicholas Lawrence, Conor Lynch. Mesenchymal stem cell-derived interleukin-28 can drive the selection of apoptosis resistant bone metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1992.

MiR-203 over-expression promotes prostate cancer cell apoptosis and reduces ADM resistance.

Extra-cellular signal regulated kinase (ERK)/mitogen activated protein kinase (MAPK) signaling pathway is widely involved in cell proliferation, apoptosis, and drug resistance. MAPK kinase 1 (MEK1) is the upstream protein kinase of ERK that can activate ERK/MAPK signaling pathway. microRNA 203 (MiR-203) down-regulation is found to be associated with prostate cancer pathogenesis. Bioinformatics analysis showed the complementary targeted relationship between miR-203 and the 3'-UTR of MEK1 mRNA. This study explored the role of miR-203 in regulating prostate cancer cell proliferation, apoptosis, and ADM resistance through affecting MEK1 expression. Dual luciferase assay confirmed the targeted relationship between miR-203 and MEK1. MiR-203, MEK1, p-ERK1/2, and B cell lymphoma 2 (Bcl-2) expressions were compared in normal prostate epithelial cells PrEC, prostate cancer cells PC-3M, and drug resistance cells PC-3M/ADM. PC-3M, PC-3M/ADM cell apoptosis and proliferation were detected by using flow cytometry under ADM treatment at IC50 concentration of PC-3M cells. PC-3M cells were cultured in vitro and divided into four groups, including microRNA-normal control (miR-NC), miR-203 mimic, small interfere NC (si-NC), and si-MEK1. MiR-203 targeted and inhibited MEK1 expression. MiR-203 levels and cell apoptosis were significantly lower, while MEK1, p-ERK1/2, Bcl-2, and cell proliferation were significantly higher in PC-3M/ADM cells compared to the PC-3M cells. MiR-203 mimic and/or si-MEK1 transfection significantly reduced MEK1, p-ERK1/2, and Bcl-2 levels, attenuated cell proliferation, induced cell apoptosis, and decreased drug resistance. MiR-203 elevation suppressed prostate cancer PC-3M cell proliferation, promoted apoptosis, and weakened ADM resistance through targeted inhibiting MEK1 expression to alleviate ERK/MAPK signaling pathway and Bcl-2 expression.

SEC-induced activation of ANXA7 GTPase suppresses prostate cancer metastasis

Annexin A7 (ANXA7) is a suppressor of tumorigenesis and metastasis in prostate cancer. Activated ANXA7 GTPase promotes prostate cancer cell apoptosis. However, the role and underlying mechanism of ANXA7 GTPase in prostate cancer metastasis have not been established. RKIP is a metastatic suppressor and downregulated in prostate cancer metastases. The binding of RKIP and its target proteins could inhibit the activation of its interactive partners. However, the effect of RKIP on ANXA7 GTPase activation is not clear. Here, we report that activation of ANXA7 GTPase by a small molecule SEC ((S)-ethyl 1-(3-(4-chlorophenoxy)-2-hydroxypropyl)-3- (4-methoxyphenyl)-1H-pyrazole-5-carboxylate) effectively inhibited prostate cancer metastasis. Mechanistically, activated ANXA7 promoted AMPK phosphorylation, leading to decreased mTORC1 activity, suppressed STAT3 nuclear translocation, and downregulation of pro-metastatic genes, including CCL2, APLN, and IL6ST. Conversely, RKIP interacted with ANXA7 and impaired activation of ANXA7 GTPase by SEC and its downstream signaling pathway. Notably, SEC treatment suppressed metastasis of prostate cancer cells in in vivo orthotopic analysis. Together, our findings provide a novel insight into how metastasis of prostate cancer with low RKIP expression is suppressed by SEC-induced activation of ANXA7 GTPase via the AMPK/mTORC1/STAT3 signaling pathway.

Abstract 253: Tetrandrine promotes prostate cancer cell apoptosis in part by up-regulation of death receptors

Abstract Introduction: Tumor necrosis factor-related apoptosis-inducing-ligand (TRAIL) is a member of the tumor necrosis factor superfamily. TRAIL, a valuable agent for cancer therapy, induces apoptosis in the majority of cancer cells, but development of resistance limits its clinical use in many malignancies including prostate cancer. We have demonstrated that Tetrandrine derivatives (TET), promote apoptosis in PCa cells in vitro and in vivo. In the present study, we investigated the ability of TET to sensitize tumor cells to TRAIL. We also investigated the role of two-death receptors- DR4 and DR5 in overcoming TRAIL resistance in prostate cancer cells. Methods: Prostate cancer cell lines LNCaP and LNCaP derived C4-2b were used for this study. Cell lines were treated with TET and TRAIL alone or in various combinations of these two for different time points. mRNA levels were quantitated via Real Time-PCR and changes in protein expression were analyzed by Western Blot. Cytotoxicity was evaluated using the Crystal violet and MTT survival assay. Cells were transfected with Lentiviral-shRNA to generate stable DR4 and DR5 single and double knockdown cells. Apoptosis assay was done using BD Pharmingen FITC Annexin-V Apoptosis Detection kit I. Results: LNCaP and C4-2b cells did not show a significant response following exposure to TRAIL. Exposure of LNCaP and C4-2b cells to TET resulted in increased mRNA and protein levels of death receptors DR4, DR5. Pretreatment of both cell lines with TET for 12h, followed by TRAIL treatment for another 24h increased the apoptosis inducing potential of TRAIL in these cells. Exposure of TET treated cells in vitro to soluble h-TRAIL in combination with TET resulted in synergistic apoptosis response. shRNA targeting DR4 and DR5 significantly reduced the levels of DR4 and DR5 protein. There was a reduced expression of DR4 and DR5 in the knock down cells in response to TET in time-dependent and concentration-dependent manner. In comparison to scrambled cells, DR4, DR5 single knockdown and DR4/DR5 double-knock down cells showed reduced sensitivity to TRAIL and TET. These cells were less apoptotic as compared to scrambled LNCaP cells as revealed by our apoptosis assay data. Taken together these data suggest that TET induced sensitization of PCa cells to TRAIL is mediated in part by DR4/DR5. Conclusion: Our results suggest that TET induces apoptosis in part by inducing the expression of DR4 and DR5, and provide the proof-of-principle for a novel therapeutic strategy to sensitize cancer cells to apoptosis. Acknowledgement: Financial support from following Sources is gratefully acknowledged: (VA Merit Award 1BX001258; NCI RO1-CA161880); Carroll W. Feist Endowed Chair Funds, FWCC support and Chair commitment LSUHSC-Shreveport). Citation Format: Gauri Shishodia, Sweaty Koul, Qin Dong, Sergey Slepenkov, Hari K. Koul. Tetrandrine promotes prostate cancer cell apoptosis in part by up-regulation of death receptors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 253.

Comparison of 4-hydroxynonenal-induced p53-mediated apoptosis in prostate cancer cells LNCaP and DU145.

Aim of the studyTo explore the mechanism of oxidative stress in the development of prostate cancer, here we compared 4-hydroxynonenal (4-HNE)- treated LNCaP (hormone-sensitive) and DU145 (hormone insensitive) cells with significant differences in sensitivity to androgen.Material and methodsThe prostate cancer cell line LNCaP and late cell line DU145 were treated with different concentrations of 4-HNE. The cell proliferation, apoptosis and mitochondrial transmembrane potential were detected at different time points, and expression of related molecules in cell proliferation and apoptosis signal pathway was analyzed by Western blot, and the over-expression of glutathione S-transferase (GSTA-4) was used to validate the changes of the effects of 4-HNE on the two kinds of cells.ResultsLNCaP cells showed greater antiproliferative and proapoptotic activities of HNE in a time- and dose-dependent manner corresponding to the activation of p53-mediated intrinsic apoptotic signaling, but JNK activation was not observed. In contrast, HNE-treated DU145 cells showed less apoptosis and proliferation was not inhibited; instead there was sustained activation of JNK, but activation of p53, p-p53, p21, Bax and caspase-3 was not observed. In addition, their effect of induction of apoptosis can be inhibited by overexpression of GSTA-4.ConclusionsThese studies suggest that 4-HNE promotes prostate cancer cell apoptosis through the p53 signaling pathway; the differences of sensitivity to 4-HNE in LNCaP and DU145 cells may be related to the androgen sensitivity of prostate cancer cells; and the 4-HNE-induced p53-mediated apoptosis signal is regulated by GSTA-4.