Elevated levels of prostate‐specific antigen (PSA) in prostate cancer cells expressing mutant p53 is associated with tumor metastasis

Downing, Sean R.; Bumak, Clare; Nixdorf, Sheri; Ow, Kim; Russell, Pamela J.; Jackson, Paul

doi:10.1002/mc.10154

Cited by 13 publications

(9 citation statements)

References 38 publications

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“…Since orthotopic tumor growth was accompanied by increased vascularisation and vascular leakage [20] ( Fig. 2) this could be another factor advancing metastatic burden [43,46]. Functional changes due to expression of cell adhesion molecules (CAM) can also modify cellular behaviour.…”

Section: Discussionmentioning

confidence: 98%

Anti-metastatic effects of liposomal gemcitabine in a human orthotopic LNCaP prostate cancer xenograft model

Jantscheff

Ziroli²,

Esser³

et al. 2009

Clin Exp Metastasis

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Fatal outcomes of prostate carcinoma (PCa) mostly result from metastatic spread rather than from primary tumor burden. Here, we monitored growth and metastatic spread of an orthotopic luciferase/GFP-expressing LNCaP PCa xenograft model in SCID mice by in vivo imaging and in vitro luciferase assay of tissues homogenates. Although the metastatic spread generally shows a significant correlation to primary tumor volumes, the susceptibility of various tissues to metastatic invasion was different in the number of affected animals as well as in absolute metastatic burden in the individual tissues. Using this xenograft model we showed that treatment with liposomal gemcitabine (GemLip) inhibited growth of the primary tumors (83.9 +/- 6.4%; P = 0.009) as well as metastatic burden in lymph nodes (95.6 +/- 24.0%; P = 0.047), lung (86.5 +/- 10.5%; P = 0.015), kidney (88.4 +/- 9.2%; P = 0.045) and stomach (79.5 +/- 6.6%; P = 0.036) already at very low efficient concentrations (8 mg/kg) as compared to conventional gemcitabine (360 mg/kg). Our data show that this orthotopic LNCaP xenograft PCa model seems to reflect the clinical situation characterized by the fact that at time of diagnosis, prostate neoplasms are biologically heterogeneous and thus, it is a useful model to investigate new anti-metastatic therapies.

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Section: Discussionmentioning

confidence: 98%

Anti-metastatic effects of liposomal gemcitabine in a human orthotopic LNCaP prostate cancer xenograft model

Jantscheff

Ziroli²,

Esser³

et al. 2009

Clin Exp Metastasis

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“…However, the emerging evidence demonstrates that p53 also plays a crucial role in regulating key stages of the metastatic progression (4,6). In PCa, although some studies have showed that mutant p53 gain of function promoted cancer development and metastasis (5,(35)(36)(37)(38), there are hardly any studies on the role of WT-p53 in PCa metastasis.We found that WT-p53 repressed invasion and migration, and suppressed EMT, which is a key step of the progression of tumor cell metastasis, and cancer stem cells properties in PC-3 cells, which might be the critical drivers of tumor progression and metastasis (16,17). Zhou et al (39,40) have found that the combined deficiency for p53 and Rb in prostate epithelium results in invasive and highly metastatic prostate carcinogenesis, and preferential malignant transformation of prostate stem cell compartment by combined deficiency by p53 and Rb indicates a critical role of these genes in the regulation of prostate stem cells during ontogenesis.…”

Section: Discussionmentioning

confidence: 99%

Wild-type p53 suppresses the epithelial-mesenchymal transition and stemness in PC-3 prostate cancer cells by modulating miR-145

Ren

Wang

Guo

et al. 2013

International Journal of Oncology

124

100

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The principal problem arising from prostate cancer (PCa) is its propensity to metastasize to bone and the mechanism(s) need to be further elucidated. The tumor suppressor p53 plays an important role in regulating the epithelial-mesenchymal transition (EMT) and cancer cell stemness, which have been proposed to play critical roles in cancer metastasis. MiR-145, a direct target of p53, represses bone metastasis of PCa and is involved in regulating EMT and cancer cell stemness. However, it is unknown whether wild‑type p53 (WT-p53) plays a role in regulating invasion, EMT and cancer cell stemness of PCa cells and whether miR-145 mediates the function of WT-p53. In the present study, we found that ectopic expression of WT-p53 inhibited the migration and invasion, and enhanced the adhesion of p53-null PC-3 cells derived from PCa bone metastasis. Furthermore, WT-p53 suppressed the expression of the mesenchymal markers fibronectin, vimentin, N-cadherin, ZEB2 and upregulated the expression of the epithelial marker E-cadherin in PC-3 cells. Moreover, WT-p53 also suppressed colony formation, tumor sphere formation and expression of CSC markers and stemness factors including CD44, Oct4, c-Myc and Klf4 in PC-3 cells. Importantly, WT-p53 upregulated the expression of miR-145, and the inhibitory effects of WT-p53 on migration, invasion, EMT and stemness of PC-3 cells were reversed by anti-miR-145. Together, our findings demonstrate that WT-p53 suppresses migration, invasion, EMT and stemness in PC-3 cells at least partially through modulating miR-145. These results suggest that loss of WT-p53 may promote the bone metastasis of PCa at least partially through repressing miR-145 to elevate EMT and stemness of cancer cells.

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“…5A) was due to the recovery of p53 (see Fig. 4A), HeLa and Caski cells were transiently transfected with a dominant negative p53 mutant (20). Expression of the dominant negative p53 effectively inhibited the ability of the calpain inhibitor to reduce viability of HeLa and Caski cells (Fig.…”

Section: A Calpain Inhibitor Restored Rb Protein Levels Repressed E6mentioning

confidence: 92%

“…Plasmids encoding Rb K810A and Rb were generated from pCDNA3.1 Rb by site-directed mutagenesis (14). Dominant negative p53 (pRc/CMV-R273H) has been described previously (20). Vector controls used pcDNA3.1 (Invitrogen).…”

mentioning

confidence: 99%

Human Papillomavirus E7 Requires the Protease Calpain to Degrade the Retinoblastoma Protein

Darnell

Schroder

Antalis

et al. 2007

Journal of Biological Chemistry

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Cervical cancers transformed by high risk human papilloma virus (HPV) express the E7 oncoprotein, which accelerates the degradation of the retinoblastoma protein (Rb). Here we show that the E7-mediated degradation of Rb requires the calciumactivated cysteine protease, calpain. E7 bound and activated -calpain and promoted cleavage at Rb 810 , with mutation of this residue preventing E7-mediated degradation. The calpain cleavage product, Rb 1-810 , was unable to mediate cell cycle arrest but retained the ability to repress E6/E7 transcription. E7 also promoted the accelerated proteasomal degradation of Infection with high risk human Papillomavirus (HPV)2 types is responsible for virtually all cases of cervical cancer, which is currently the second most common cause of death from cancer among women worldwide (1). Vaccination will likely have a substantial impact; however, current modeling suggests that it may take 40 -50 years to reach an Ϸ50% reduction in mortality (2). Integration of part of the HPV genome is believed to be central to the transformation process (3) and often results in the increased expression of the two viral oncoproteins, E6 and E7. A principle activity of E6 and E7 is promotion of the accelerated degradation of p53 and the retinoblastoma protein (Rb), respectively (4, 5). Hypophosphorylated Rb binds the E2F transcription factor, resulting in repression of E2F-dependent gene transcription and G 1 cell cycle arrest (6). The promotion of Rb degradation mediated by E7 is believed to involve a two-step process (7). First, E7 binds hypophosphorylated Rb (8), which leads to the displacement of E2F and entry into the cell cycle. How E2F is displaced by E7 remains unclear as E7 and E2F binding sites on Rb have recently been shown to be quite distinct (9). The second step involves E7 targeting Rb for accelerated degradation via the proteasome (10 -12). A new insight into the mechanism of E7-mediated degradation of Rb was recently provided by our observation that the serine protease inhibitor SerpinB2 was able to inhibit E7-mediated degradation of Rb in HeLa cells (13,14). There are no reports that SerpinB2 inhibits the proteasome, and it has recently emerged that SerpinB2 inhibits calpain-mediated degradation of Rb. 3Calpains represent a group of calcium-activated cysteine proteases, two of which, -calpain and m-calpain, are ubiquitously expressed and found both in the cytoplasm and the nucleus (15). Herein we provide evidence that the first step in the E7-mediated degradation of Rb involves calpain cleavage. E7 was shown to bind and activate -calpain and promoted cleavage of full-length Rb 1-928 to yield Rb . Rb 1-810 was unable to promote cell cycle arrest, suggesting that this cleavage event was sufficient to displace E2F from Rb. The second step involved the promotion by E7 of the proteasomal degradation of Rb . Calpain inhibitors are being developed for a number of diseases including cancer (16, 17) and were able to inhibit E7-mediated degradation of Rb. They also reduced the viability of HPV-tr...

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Elevated levels of prostate‐specific antigen (PSA) in prostate cancer cells expressing mutant p53 is associated with tumor metastasis

Cited by 13 publications

References 38 publications

Anti-metastatic effects of liposomal gemcitabine in a human orthotopic LNCaP prostate cancer xenograft model

Anti-metastatic effects of liposomal gemcitabine in a human orthotopic LNCaP prostate cancer xenograft model

Wild-type p53 suppresses the epithelial-mesenchymal transition and stemness in PC-3 prostate cancer cells by modulating miR-145

Human Papillomavirus E7 Requires the Protease Calpain to Degrade the Retinoblastoma Protein

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