Binding of α(2)M* to prostate cancer cell surface GRP78 upregulates mTORC1 and mTORC2 activation and promotes protein synthesis in the prostate cancer cells.
We previously reported that advanced prostate cancer (PCa) patients with multiple distant bone metastases had markedly decreased serum α2M levels (<20 mg/dl) and no detection of α2M by immunoelectrophoresis (defined as α2M deficiency).
PSA-alpha-2-macroglobulin complex is enzymatically active in the serum of patients with advanced prostate cancer and can degrade circulating peptide hormones.
As expected, lycopene treatment (2.5-10 μM) significantly inhibited the proliferation of LNCaP cells during incubation for 96 h. Lycopene significantly increased the protein and mRNA expression of PPARγ and LXRα at 24 and 48 h, while the increased in the expression of ATP-binding cassette transporter 1 (ABCA1) was only evident 96 h. In addition, lycopene significantly decreased cellular total cholesterol levels and increased apoA1 protein expression at 96 h. Incubation of LNCaP cells with lycopene (10 μM) in the presence (20 μM) of a specific antagonist of PPARγ (GW9662) and LXRα (GGPP) restored the proliferation of LNCaP cells to the control levels and significantly suppressed protein expression of PPARγ and LXRα as well as increased cellular total cholesterol levels.
In human prostate biopsy samples, ABCA1 mRNA expression was ∼2-fold higher in the androgen deprivation therapy group than in subjects with benign prostatic hyperplasia or pretreatment prostate cancer groups.
Cytotoxicity assays suggested a role for ABCA2 in estramustine and estradiol resistance, and overexpression of ABCA2 is seen in an estramustine-resistant prostate carcinoma line.
These data suggest that drug resistance in human prostate cancer may be multifactorial, with MRP and LRP frequently expressed in prostate cancer cells before antineoplastic drug treatment and P-gp expression occasionally acquired after drug exposure.
The study was focused on the inhibition of MDR by blocking the ADR1 gene expression and through the inhibition of the pump-function of mdr-p-glycoprotein, in human breast cancer cell lines expressing mrp and prostate cancer cell line (PC-3).
Hypermethylation was more frequent in PCa than in BPH tissues (EDNRB, 100% versus 88%; TIG1, 96% versus 12%; RARbeta, 95% versus 35%; GSTP1, 93% versus 15%; APC, 80% versus 50%; MDR1, 80% versus 31%; PTGS2, 68% versus 15%; Reprimo, 59% versus 19%; and Annexin2, 4% versus 0%).
Those stem-like prostate cancer cells show high expression of ABCB1, which encodes multidrug resistance-related protein P-glycoprotein, leading to the Doc-resistance in prostate cancer.
Steroid derivatives were studied for their growth-inhibitory effect, cytotoxicity, reversal of multidrug resistance, apoptosis induction, and interaction with doxorubicin on multidrug resistant human ATP-binding cassette, sub-family B, member 1 (ABCB1) gene-transfected mouse T-lymphoma cell line, and human PC-3 and LNCaP prostate cancer cell lines in vitro.
Because of a possible beneficial effect of a combination of ketoconazole and a chemotherapeutic drug in multidrug resistant cancers, we examined a panel of 11 prostate carcinoma tissues for the expression of the MDR1 gene by an RNA-PCR assay.
Taken together, these results provide strong evidence that TPL overcomes MDR in prostate cancer cells by downregulating MDR1 expression, and suggest that TPL is a promising agent for prostate cancer therapy, especially for chemoresistant prostate cancer.
We hypothesize that early in prostate cancer progression, increased expression of YB-1 may increase P-gp activity which may in turn lower androgen levels in the prostate tumor cells.
These findings suggest that CpG hypermethylation of MDR1 promoter is a frequent event in prostate cancer and is related to disease progression via increased cell proliferation in prostate cancer cells.