Inhibition of angiogenesis and MMP-9 expression by PCK3145 is mediated through targeting of the Akt signaling pathway
Bibliographic record
Abstract
Proc Amer Assoc Cancer Res, Volume 47, 2006 4369 Adenocarcinoma of the prostate gland is among the leading malignancies in men with high morbidity and mortality rates due to the development of skeletal metastases. PSP-94, one of the three predominant proteins produced by normal prostate gland, is absent in late stage prostate cancer which supports its potential tumor suppressor role. Previous studies carried out in our laboratory have shown the ability of PSP-94 and PCK3145 (amino acids 31–45 of PSP-94) to suppress prostate cancer growth and development of skeletal metastases. Recently, a phase IIa clinical trial carried out in patients with hormone refractory prostate cancer and treated with PCK3145 resulted in disease stabilization. Furthermore, treatment with PCK3145 caused either a stabilization or reduction of MMP-9 levels in these patients. In the current study we evaluated the possible mechanism(s) of action of PCK3145. For these studies, rat prostate cancer MatLyLu cells were treated with different concentrations of PCK3145. Total cellular RNA and conditioned media were collected. PCK3145 treatment resulted in a significant dose dependent reduction in MMP-9 mRNA and protein levels as analyzed by real time RT-PCR, Western blot analysis and zymography. No significant effect on MMP-2 production was seen. Furthermore, treatment of MatLyLu cells with different doses of PCK3145 resulted in a dose dependent reduction in the levels of p-Erk and p-Akt. For in vivo studies, male Copenhagen rats were inoculated either subcutaneously or via intracardiac injections with MatLyLu cells to develop primary tumor growth or experimental skeletal metastases, respectively. Animals were treated with different doses of PCK3145 (1.0–100.0μg/kg) and at the end of the study their tumors were excised and analyzed. PCK3145 caused a dose dependent reduction in tumor volume and a significant decrease in MMP-9 production and neovascularization as assessed by immunohistochemical analysis of primary tumors. These effects were due to the ability of PCK3145 to inhibit p-Erk and p-Akt production by primary tumors. Similarly PCK3145 treatment caused a significant reduction in skeletal tumor burden, delay in hind limb paralysis and inhibition of MMP-9 expression. Collectively, the results obtained from these studies show that the ability of PCK3145 to reduce tumor growth and delay the development of skeletal metastases is in part due to its ability to reduce the levels of MMP-9 and tumor angiogenesis, effects which are mediated through the reduction of active Akt kinase previously reported to modulate the expression of several genes including MMP-9. The results obtained from these studies provide evidence for the mechanism of action of PCK3145 which can be selectively targeted alone or in combination with other therapeutic agents for prostate cancer patients.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".