Androgen stimulates glycolysis for de novo lipid synthesis by increasing the activities of hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 in prostate cancer cells

Up-regulation of lipogenesis by androgen is one of the most characteristic metabolic features of LNCaP prostate cancer cells. The present study revealed that androgen increases glucose utilization for de novo lipogenesis in LNCaP cells through the activation of HK2 (hexokinase 2) and activation of the cardiac isoform of PFKFB2 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase). Activation of PKA (cAMP-dependent protein kinase) by androgen increased phosphorylation of CREB [CRE (cAMP-response element)-binding protein], which in turn bound to CRE on the promoter of the HK2 gene resulting in transcriptional activation of the HK2 gene. Up-regulation of PFKFB2 expression was mediated by the direct binding of ligand-activated androgen receptor to the PFKFB2 promoter. The activated PI3K (phosphoinositide 3-kinase)/Akt signalling pathway in LNCaP cells contributes to the phosphorylation of PFKFB2 at Ser466 and Ser483, resulting in the constitutive activation of PFK-2 (6-phosphofructo-2-kinase) activity. Glucose uptake and lipogenesis were severely blocked by knocking-down of PFKFB2 using siRNA (small interfering RNA) or by inhibition of PFK-2 activity with LY294002 treatment. Taken together, our results suggest that the induction of de novo lipid synthesis by androgen requires the transcriptional up-regulation of HK2 and PFKFB2, and phosphorylation of PFKFB2 generated by the PI3K/Akt signalling pathway to supply the source for lipogenesis from glucose in prostate cancer cells.

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Modulation of de Novo Lipogenesis Improves Response to Enzalutamide Treatment in Prostate Cancer

Cancers ◽

10.3390/cancers12113339 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3339

Author(s):

Mohamed Amine Lounis ◽

Benjamin Péant ◽

Kim Leclerc-Desaulniers ◽

Dwaipayan Ganguli ◽

Caroline Daneault ◽

...

Keyword(s):

Prostate Cancer ◽

Fatty Acids ◽

Cancer Cells ◽

De Novo ◽

Saturated Fatty Acids ◽

Monounsaturated Fatty Acids ◽

Important Change ◽

De Novo Lipogenesis ◽

Prostate Cancer Cells ◽

Aggressive Prostate Cancer

De novo lipogenesis (DNL) is now considered as a hallmark of cancer. The overexpression of key enzymes of DNL is characteristic of both primary and advanced disease and may play an important role in resistance to therapies. Here, we showed that DNL is highly enhanced in castrate resistant prostate cancer (CRPC) cells compared to hormone sensitive and enzalutamide resistant cells. This observation suggests that this pathway plays an important role in the initiation of aggressive prostate cancer and in the development of enzalutamide resistance. Importantly, here we show that both prostate cancer cells sensitive and resistant to enzalutamide are dependent on DNL to proliferate. We next combined enzalutamide with an inhibitor of Stearoyl CoA Desaturase 1 (SCD1), an important enzyme in DNL, and observed significantly reduced tumor growth caused by the important change in tumoral lipid desaturation. Our findings suggest that the equilibrium between monounsaturated fatty acids and saturated fatty acids is essential in the establishment of the more aggressive prostate cancer phenotype and that the combination therapy induces a disruption of this equilibrium leading to an important decrease of cell proliferation. These findings provide new insights into the role of DNL in the progression of prostate cancer cells. The study also provides the rationale for the use of an inhibitor of SCD1 in combination with enzalutamide to improve response, delay enzalutamide resistance and improve disease free progression.

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Expression of a hyperactive androgen receptor leads to androgen-independent growth of prostate cancer cells

Journal of Molecular Endocrinology ◽

10.1677/jme-07-0158 ◽

2008 ◽

Vol 41 (1) ◽

pp. 13-23 ◽

Cited By ~ 8

Author(s):

Chen-Lin Hsieh ◽

Changmeng Cai ◽

Ahmed Giwa ◽

Aaronica Bivins ◽

Shao-Yong Chen ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Cells ◽

Transcriptional Activation ◽

Soluble Guanylyl Cyclase ◽

Growth Conditions ◽

Lncap Cells ◽

Prostate Cancer Cells ◽

Transcriptional Activation Domain ◽

Androgen Independent

Cellular changes that affect the androgen receptor (AR) can cause prostate cancer to transition from androgen dependent to androgen independent, which is usually lethal. One common change in prostate tumors is overexpression of the AR, which has been shown to lead to androgen-independent growth of prostate cancer cells. This led us to hypothesize that expression of a hyperactive AR would be sufficient for androgen-independent growth of prostate cancer cells. To test this hypothesis, stable lune cancer prostate (LNCaP) cell lines were generated, which express a virion phosphoprotein (VP)16-AR hybrid protein that contains full-length AR fused to the strong viral transcriptional activation domain VP16. This fusion protein elicited as much as a 20-fold stronger transcriptional activity than the natural AR. Stable expression of VP16-AR in LNCaP cells yielded androgen-independent cell proliferation, while under the same growth conditions the parental LNCaP cells exhibited only androgen-dependent growth. These results show that expression of a hyperactive AR is sufficient for androgen-independent growth of prostate cancer cells. To study the molecular basis of this enhanced growth, we measured the expression of soluble guanylyl cyclase-α1 (sGCα1), a subunit of the sGC, an androgen-regulated gene that has been shown to be involved in prostate cancer cell growth. Interestingly, the expression of sGCα1 is androgen independent in VP16-AR-expressing cells, in contrast to its androgen-induced expression in control LNCaP cells. RNAI-dependent inhibition of sGCα1 expression resulted in significantly reduced proliferation of VP16-AR cells, implicating an important role for sGCα1 in the androgen-independent growth of these cells.

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Expression and Function of Lysophosphatidic Acid LPA1 Receptor in Prostate Cancer Cells

Endocrinology ◽

10.1210/en.2005-1635 ◽

2006 ◽

Vol 147 (10) ◽

pp. 4883-4892 ◽

Cited By ~ 55

Author(s):

Rishu Guo ◽

Elizabeth A. Kasbohm ◽

Puneeta Arora ◽

Christopher J. Sample ◽

Babak Baban ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Androgen Receptor ◽

Cancer Cells ◽

Lysophosphatidic Acid ◽

Cell Cycle Progression ◽

Receptor Activation ◽

Lncap Cells ◽

Prostate Cancer Cells ◽

And Migration

The bioactive phospholipid lysophosphatidic acid (LPA) promotes cell proliferation, survival, and migration by acting on cognate G protein-coupled receptors named LPA1, LPA2, and LPA3. We profiled gene expression of LPA receptors in androgen-dependent and androgen-insensitive prostate cancer cells and found that LPA1 gene is differentially expressed in androgen-insensitive and LPA-responsive but not androgen-dependent and LPA-resistant cells. In human prostate specimens, expression of LPA1 gene was significantly higher in the cancer compared with the benign tissues. The androgen-dependent LNCaP cells do not express LPA1 and do not proliferate in response to LPA stimulation, implying LPA1 transduces cell growth signals. Accordingly, stable expression of LPA1 in LNCaP cells rendered them responsive to LPA-induced cell proliferation and decreased their doubling time in serum. Implantation of LNCaP-LPA1 cells resulted in increased rate of tumor growth in animals compared with those tumors that developed from the wild-type cells. Growth of LNCaP cells depends on androgen receptor activation, and we show that LPA1 transduces Gαi-dependent signals to promote nuclear localization of androgen receptor and cell proliferation. In addition, treatment with bicalutamide inhibited LPA-induced cell cycle progression and proliferation of LNCaP-LPA1 cells. These results suggest the possible utility of LPA1 as a drug target to interfere with progression of prostate cancer.

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Calcitriol-Induced Apoptosis in LNCaP Cells Is Blocked By Overexpression of Bcl-21

Endocrinology ◽

10.1210/endo.141.1.7289 ◽

2000 ◽

Vol 141 (1) ◽

pp. 10-17 ◽

Cited By ~ 89

Author(s):

Sarah E. Blutt ◽

Timothy J. McDonnell ◽

Tara C. Polek ◽

Nancy L. Weigel

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Vitamin D ◽

Cancer Cells ◽

Mineral Metabolism ◽

Lncap Cells ◽

Prostate Cancer Cells ◽

Apoptotic Pathway ◽

Induced Apoptosis

Abstract While the role of vitamin D in bone and mineral metabolism has been investigated extensively, the role of the vitamin D receptor in other tissues is less well understood. 1,25-dihydroxyvitamin D3 (calcitriol) can act as a differentiating agent in normal tissues and can inhibit the growth of many cancer cell lines including LNCaP prostate cancer cells. We have shown previously that calcitriol causes LNCaP cell accumulation in the G0/G1 phase of the cell cycle. In this study, we demonstrate that calcitriol also induces apoptosis of LNCaP cells. The calcitriol-induced apoptosis is accompanied by a down-regulation of Bcl-2 and Bcl-XL proteins, both of which protect cells from undergoing apoptosis. Other proteins important in apoptotic control, Bax, Mcl-1, and Bcl-Xs, are unaffected by calcitriol treatment. We find that overexpression of Bcl-2 blocks calcitriol-induced apoptosis and reduces, but does not eliminate, calcitriol-induced growth inhibition. We conclude that both regulation of cell cycle and the apoptotic pathway are involved in calcitriol action in prostate cancer cells.

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Inhibition of Prostate Cancer Cell Growth by Human Secreted PDZ Domain-Containing Protein 2, a Potential Autocrine Prostate Tumor Suppressor

Endocrinology ◽

10.1210/en.2006-0207 ◽

2006 ◽

Vol 147 (11) ◽

pp. 5023-5033 ◽

Cited By ~ 10

Author(s):

C. W. Tam ◽

A. S. Cheng ◽

R. Y. M. Ma ◽

K.-M. Yao ◽

S. Y. W. Shiu

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Caspase 3 ◽

Pdz Domain ◽

Human Prostate ◽

Human Prostate Cancer ◽

Lncap Cells ◽

Prostate Cancer Cells ◽

Autocrine Growth ◽

Endogenous Expression

A possible role of the PDZ domain-containing protein 2 (PDZD2) in prostate tumorigenesis has been suggested. Besides, PDZD2 is posttranslationally cleaved by a caspase-dependent mechanism to form a secreted PDZ domain-containing protein 2 (sPDZD2) with unknown functions in humans. In this study, we demonstrate the endogenous expression of PDZD2 and secretion of sPDZD2 in cancerous DU145, PC-3, 22Rv1, LNCaP, and immortalized RWPE-1 prostate epithelial cells. Inhibition of endogenous sPDZD2 production and secretion by DU145, PC-3, 22Rv1, and RWPE-1 cells via the caspase-3 inhibitor Z-DEVD-FMK resulted in increased cell proliferation, which was abrogated by treatment with exogenous recombinant sPDZD2. Whereas sPDZD2-induced antiproliferation in DU145, PC-3, and 22Rv1 cells, it induced apoptosis in LNCaP cells. The data suggest that endogenous sPDZD2, produced by caspase-3-mediated cleavage from PDZD2, may function as a novel autocrine growth suppressor for human prostate cancer cells. The antiproliferative effect of sPDZD2 was apparently mediated through slowing the entry of DU145, PC-3, and 22Rv1 cells into the S phase of the cell cycle. In DU145 cells, this can be attributed to stimulated p53 and p21CIP1/WAF1 expression by sPDZD2. On the other hand, the apoptotic effect of sPDZD2 on LNCaP cells was apparently mediated via p53-independent Bad stimulation. Together our results indicate the presence of p53-dependent and p53-independent PDZD2/sPDZD2 autocrine growth suppressive signaling pathways in human prostate cancer cells and suggest a novel therapeutic approach of harnessing the latent tumor-suppressive potential of an endogenous autocrine signaling protein like sPDZD2 to inhibit prostate cancer growth.

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The transcriptomics of de novo androgen biosynthesis in prostate cancer cells following androgen reduction

Cancer Biology & Therapy ◽

10.4161/cbt.9.12.11876 ◽

2010 ◽

Vol 9 (12) ◽

pp. 1033-1042 ◽

Cited By ~ 13

Author(s):

Jinrong Cheng ◽

Yue Wu ◽

James L. Mohler ◽

Clement Ip

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

De Novo ◽

Prostate Cancer Cells

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p53 Is Required for 1,25-Dihydroxyvitamin D3-Induced G0 Arrest But Is Not Required for G1 Accumulation or Apoptosis of LNCaP Prostate Cancer Cells

Endocrinology ◽

10.1210/en.2001-210109 ◽

2003 ◽

Vol 144 (1) ◽

pp. 50-60 ◽

Cited By ~ 43

Author(s):

Tara C. Polek ◽

LaMonica V. Stewart ◽

Elizabeth J. Ryu ◽

Michael B. Cohen ◽

Elizabeth A. Allegretto ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Cancer Cells ◽

Cell Lines ◽

Dominant Negative ◽

Lncap Cells ◽

Prostate Cancer Cells ◽

Dihydroxyvitamin D3 ◽

1,25 Dihydroxyvitamin D3 ◽

Induction Of Apoptosis

Abstract 1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] is an effective agent for inhibiting the growth of prostate cancer cells including LNCaP and PC-3 cell lines. However, the extent of growth inhibition in these cell lines differs because LNCaP cells are much more responsive than PC-3 cells. Previous studies in LNCaP cells have shown that 1,25-(OH)2D3 treatment results in G0/G1 cell cycle accumulation, loss of Ki67 expression, and induction of apoptosis. One difference between the two cell lines is that PC-3 cells lack functional p53, a protein that plays roles both in cell cycle regulation and induction of apoptosis. In this study, the role of p53 in 1,25-(OH)2D3 action was examined using the p53-negative PC-3 cells and a line of LNCaP cells, called LN-56, in which p53 function was shut off using a dominant negative p53 fragment. We found that treatment with 1,25-(OH)2D3 extensively inhibits growth of LN-56 prostate cancer cells lacking p53, but in contrast to the parental LNCaP cells, the LN-56 cells recover rapidly. Moreover, in prostate cancer cells, the synergism between 1,25-(OH)2D3 and 9-cis retinoic acid appears to be dependent on the presence of functional p53; however, 1,25-(OH)2D3-mediated induction of G1 cell cycle accumulation and induction of apoptosis is not.

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