CN107383173B - Polypeptide for inducing apoptosis of prostate cancer cells and application thereof - Google Patents
Polypeptide for inducing apoptosis of prostate cancer cells and application thereof Download PDFInfo
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- CN107383173B CN107383173B CN201710667184.0A CN201710667184A CN107383173B CN 107383173 B CN107383173 B CN 107383173B CN 201710667184 A CN201710667184 A CN 201710667184A CN 107383173 B CN107383173 B CN 107383173B
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Abstract
The present invention relates to a polypeptide inducing apoptosis of prostate cancer cells and its use in the preparation of a medicament for treating prostate cancer in a subject.
Description
Technical Field
The invention relates to the technical field of medical biology, in particular to a polypeptide for inducing apoptosis of prostate cancer cells and application thereof in preparation of a medicament for treating prostate cancer in a subject.
Background
Prostate cancer is an epithelial malignancy that occurs in the prostate gland, has a high incidence and a high mortality, and is one of the most common malignancies in men. The cause of prostate cancer is currently unknown and may be related to a variety of factors, including genetics and environment. Like other human tumors, inflammation and immunosuppression play important roles in the development and progression of prostate cancer.
The current research suggests that the host components interacting with tumors may participate in the formation of immunosuppressive microenvironments for prostate cancer development and progression, and a large body of evidence suggests that prostate cancer is immunologically relevant, and the existence of several tumor-associated antigens in the prostate further demonstrates its feasibility, mainly Prostate Specific Membrane Antigen (PSMA), prostate hepatocyte antigen (PSCA), Prostate Acid Phosphatase (PAP), etc. The molecular targeting drugs designed aiming at the relevant antigens can selectively kill or inhibit tumor cells without damaging normal cells, thereby having important research significance and wide application prospect.
PSMA is a type ii transmembrane glycoprotein present in the cell membrane of prostate epithelial cells and consists essentially of three parts: an extracellular portion (707 amino acids), a transmembrane portion (24 amino acids) and an intracellular portion (19 amino acids). PSMA is involved in signal transduction based on such a transmembrane structure, so that a signal of a cell surface protein can be transmitted into a cell, and has a receptor function to exert endocytosis, and has characteristics of promoting cell migration and folate hydrolase and carboxypeptidase.
Because PSMA is highly expressed in prostate cancer epithelial cells and is not expressed or is low expressed in normal tissue endothelial cells, particularly in patients with advanced prostate cancer and metastatic prostate cancer, the increase of PSMA is particularly obvious, which makes PSMA an important target molecule for diagnosis and treatment of prostate cancer. Since the first development of PSMA monoclonal antibody 7E11-C5 by Horoszewicz et al in 1987, a series of PSMA-directed monoclonal antibodies J415, J591, J533 were isolated and purified. Early 7E11 recognized only epitopes within PSMA cells and was unable to bind to live cells. J591, however, not only recognizes extracellular epitopes of PSMA, but also binds living PSMA-expressing cells. This is mainly because the extracellular domain of PSMA can be invaginated by the motif MXXXL to increase binding and uptake of J591 by cells.
The specificity of the derived specific killer prostate cancer cells based on the antibodies provides an important research idea for targeted therapy of prostate cancer. In particular, in recent years, a plurality of epitopes capable of binding to polypeptides have been found in the intracellular and extracellular regions of PSMA. The polypeptide capable of being combined with the epitope, in particular the polypeptide drug combined with the extracellular region epitope has important significance for treating the prostatic cancer.
Based on a structural domain of PSMA outside a membrane, which can be identified with drugs, researchers design and synthesize a series of methotrexate conjugates which can be activated by PSMA, so that PSMA can be promoted to play an exopeptidase role, methotrexate is released, and a tumor killing effect is achieved, but expected effects cannot be achieved due to overlarge molecules of the conjugates, toxicity of the methotrexate and the like.
On the other hand, the deletion of the autophagy-related gene Beclin1 is the mechanism of the reduction of autophagy and the enhancement of anti-apoptosis ability of tumor cells. Increasing the expression of Beclin1 is helpful for enhancing autophagy of tumor cells and reducing the anti-apoptosis capacity of the tumor cells. The Beclin1 protein also contains three parts, namely three domains of BH3(Bcl-2-homology-3), a central-helical region (CCD), and an evolutionary conserved region (ECD). Wherein the ECD domain is crucial for Beclin1 to play the functions of regulating autophagy and inhibiting tumors. Research shows that the fusion protein containing the Beclin1 ECD structural domain can obviously improve the apoptosis rate of prostate cancer cells, and apoptotic cells gradually increase along with the increase of the concentration of the ECD fusion protein.
Based on the analysis of the amino acid sequence of Beclin1 and the combination of J591 with the hypervariable region sequence of PSMA, we studied and designed polypeptides capable of specifically recognizing PSMA and accelerating apoptosis of PSMA positive cells.
Disclosure of Invention
The invention aims to provide a polypeptide capable of inducing apoptosis of prostate cancer cells through PSMA and a related medicine.
In a first aspect, the present invention provides a polypeptide that induces apoptosis of prostate cancer cells, the amino acid sequence of the polypeptide comprising SEQ ID NO: 1
(WTKALKFXXKLWGLAWVSHFSVGS), wherein X is any amino acid.
In an embodiment of the invention, the amino acid sequence of the polypeptide is SEQ ID NO: 1.
in an embodiment of the invention, the amino acid sequence of the polypeptide is SEQ ID NO: 2-10, the specific sequence is as follows:
SEQ ID NO：2：WTKALKFMLTNLKWGLAWVSHFSVGS；
SEQ ID NO：3：WTKALKFMLNTLKWGLAWVSHFSVGS；
SEQ ID NO：4：WTKALKFMAHILKWGLAWVSHFSVGS；
SEQ ID NO：5：WTKALKFMGCPLKWGLAWVSHFSVGS；
SEQ ID NO：6：WTKALKFMSTMLKWGLAWVSHFSVGS；
SEQ ID NO：7：WTKALKFMDQWLKWGLAWVSHFSVGS；
SEQ ID NO：8：WTKALKFMYKKLKWGLAWVSHFSVGS；
SEQ ID NO：9：WTKALKFMFVSLKWGLAWVSHFSVGS；
SEQ ID NO：10：WTKALKFMRTELKWGLAWVSHFSVGS。
in a second aspect, the invention provides the use of a polypeptide as described in the first aspect in the manufacture of a medicament for the treatment of prostate cancer in a subject.
In an embodiment of the invention, the medicament can be administered orally, intravenously, intraarterially, subcutaneously or intramuscularly.
In an embodiment of the invention, the medicament is formulated as a solid or physiologically acceptable liquid carrier.
Has the advantages that:
compared with a series of existing monoclonal antibodies, polypeptides, compounds and the like capable of inhibiting PSMA, the polypeptide has stronger capability of inducing apoptosis of prostate cancer cells and better treatment effect on the prostate cancer.
Drawings
The above and other objects, features and advantages of the present invention will become more apparent from the following description of the embodiments of the present invention with reference to the accompanying drawings, in which:
figure 1 shows the mass concentrations of SEQ ID NO: 2 inhibiting the migration of the prostate cancer cell line LNcap.
Figure 2 shows the mass concentrations of SEQ ID NO: 2 polypeptide has the function of regulating and controlling the expression of apoptosis inhibiting gene Bcl-2 and autophagy related gene Atg5 in prostate cancer cell strain LNcap.
Figure 3 shows the mass concentrations of SEQ ID NO: 2 polypeptide regulating and controlling p-AKT expression level in prostate cancer cell strain LNcap cell.
Figure 4 shows the mass concentrations of SEQ ID NO: 2 polypeptide and J591 monoclonal antibody on the tumor inhibition effect of prostate cancer mice.
Detailed Description
The present invention will be described below based on examples, but the present invention is not limited to only these examples.
EXAMPLE 1 polypeptide Synthesis
The polypeptide amino acid sequence is SEQ ID NO: 2: WTKALKFMLTNLKWGL AWVSHFSVGS
The synthesis was entrusted to Nanjing King Shirui Biotech Co., Ltd. After dissolving the DMSO, storing the mixture at-80 ℃ for later use.
Example 3
Taking LNcap cells, adjusting the cell concentration to 1x106One per ml. 100. mu.l of 1 × 10 concentration were inoculated into the upper chamber of a Cornng Transwell plate6LNcap cells per mL, and different mass concentrations (0, 2, 10, 50, 100. mu.g/mL) of polypeptide were added. Adding 500 μ l of RPMI1640 medium containing 40% FBS into the lower chamber, culturing in an incubator for 18h after plating, taking out the lower chamber and discarding the medium in the upper chamber, fixing with 4% paraformaldehyde solution, staining with crystal violet, and transferring to the cells at the lower layer of the microporous membrane in a counting frame under an inverted microscope under an amplification of 200 times. On average, 10 fields were counted per cell. The migration ability of the cells was analyzed by averaging.
As shown in fig. 1, the polypeptide of the present invention can effectively inhibit the migration ability of LNcap cells, and the migration ability of LNcap cells is gradually decreased with increasing concentration of the polypeptide in a dose-dependent manner.
Example 4
LNcap cells were cultured at 5 × 105The density of each well is inoculated in a 6-well plate, and after 24h of culture under the conditions of 37 ℃ and 5% CO2, polypeptides with different mass concentrations (0, 2, 10, 50 and 100 mu g/mL) are respectively added. And continuously culturing for 48h, collecting cells, extracting RNA, performing reverse transcription to form cDNA, and detecting the expression of an apoptosis inhibiting gene Bcl-2 and an autophagy related gene Atg5 by qPCR with GAPDH as an internal reference.
The primer sequences are respectively as follows:
GAPDH Forward:5’-GGAGCGAGATCCCTCCAAAAT-3’，
GAPDH Reverse:GGCTGTTGTCATACTTCTCATGG-3’；
Bcl-2 Forward:GGTGGGGTCATGTGTGTGG-3’，
Bcl-2 Reverse:CGGTTCAGGTACTCAGTCATCC-3’；
Atg5 Forward:5’-AAAGATGTGCTTCGAGATGTGT-3’,
Atg5 Reverse:5’-CACTTTGTCAGTTACCAACGTCA-3’。
as shown in FIG. 2, the polypeptide of the present invention can accelerate the apoptosis of LNcap cells by down-regulating the expression of apoptosis inhibitor gene Bcl-2 and up-regulating the expression of autophagy-related gene Atg 5.
Example 5
PSMA can activate the PI3K/AKT signaling pathway by upregulating AKT phosphorylation levels, increasing the proliferation and metastasis of prostate cancer cells.
The prostate cancer cell line LNcap cell line 5 × 105The cells were cultured in 6-well plates at a density of one cell per well, and then cultured at 37 ℃ for 24 hours in 5% CO2, and then polypeptides at different mass concentrations (0, 2, 10, 50, 100. mu.g/mL) were added, and the cells were collected after further culturing for 48 hours.
After washing 3 times with 4 ℃ precooled PBS, 200. mu.L of RIPA lysis buffer containing protease inhibitor and phosphatase inhibitor at 4 ℃ was added to resuspend the cells and lyse them on ice for 20 min. Centrifuging to collect supernatant protein solution, adding 150 μ l protein solution into 37.5 μ l 5 × protein buffer, boiling at 100 deg.C for 5min, and storing at 4 deg.C.
Adding the prepared protein solution into gel for electrophoresis, and performing electrophoresis at a voltage of 60V for 5min and then at a voltage of 80V for 60 min. And (5) after electrophoresis is finished, membrane switching is carried out for 100V and 2 h. After the completion, the membrane was taken out from the electric rotary tank, slightly rinsed by TBST, immersed in a confining liquid (containing 5% skimmed milk powder), and slowly shaken for 1 h. The membranes containing the target protein were transferred separately into a self-sealing bag containing 4ml of a primary Antibody (Rabbit Phospho-AKT1(Ser473) Antibody), and transferred to 4 ℃ overnight at 50rpm on a horizontal shaker for 1 h. The next day the membranes were removed and rinsed four times with TBST. The membrane to which the target protein was transferred and the membrane to which the internal reference protein was transferred were placed in a number 2 self-sealing bag, respectively, and a diluted (1: 5000) secondary antibody (coat anti-rabbitigg (H + L) second condardanyantibody) corresponding to the primary antibody was added, gently shaken at room temperature for one hour, and both the primary and secondary antibodies were purchased from eBioscience. After the secondary antibody incubation was complete, the membranes were rinsed four times with PBST. Adding color developing agent to take color and photograph in dark.
As a result, as shown in FIG. 3, the expression level of p-AKT in LNcap cells gradually decreased with the increase in the concentration of the polypeptide. The polypeptide can inhibit PI3K/AKT signal channel by inhibiting phosphorylation of AKT, thereby inhibiting proliferation and transfer of PSMA.
Example 6
The animal model detects the tumor inhibiting effect of the polypeptide in vivo. Taking 6-8 week old males42C 57BL/6 nude mice, the LNcap cell concentration in the logarithmic growth phase was adjusted to 2X107Each 100ul of the mice was inoculated subcutaneously into the right forelimb axilla of C57BL/6 nude mice. The tumor volume of the nude mice reaches 50-100 mm after 1-2 weeks3At this time, the nude mice were randomly divided into 6 groups of 7 mice each. Respectively 0, 2, 10, 50, 100 mu g/kg of polypeptide group and 100 mu g/kg of J591 monoclonal antibody group. The 0. mu.g/kg group served as a negative control group and was replaced by an equal volume of DMSO. Each group of polypeptides and J591 were diluted to 200ul with physiological saline and injected via tail vein. After 4 times of continuous administration once every 2 days, the survival number of nude mice was observed and the survival rate was counted.
As shown in FIG. 4, the survival time of the nude mice was gradually prolonged with the increase of the polypeptide concentration, and the survival time of the mice was the longest at the polypeptide concentration of 100. mu.g/kg. Compared with the J591 monoclonal antibody group, the polypeptide of the invention has better effect than that of the J591 monoclonal antibody when the concentration is 100 mug/kg.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Sequence listing
<110> Shenzhen Taihua cell engineering Limited
<120> polypeptide for inducing apoptosis of prostate cancer cells and application thereof
<130>20170806
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Claims (4)
1. A polypeptide for inducing apoptosis of prostate cancer cells, the amino acid sequence of the polypeptide is SEQ ID NO: 2, respectively.
2. Use of a polypeptide as claimed in claim 1 in the manufacture of a medicament for treating prostate cancer in a subject.
3. The use of claim 2, wherein the medicament is capable of being administered orally, intravenously, intraarterially, subcutaneously, or intramuscularly.
4. Use according to claim 2 or 3, wherein the medicament is formulated as a solid or physiologically acceptable liquid carrier.
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| CN201710667184.0A CN107383173B (en) | 2017-08-07 | 2017-08-07 | Polypeptide for inducing apoptosis of prostate cancer cells and application thereof |
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| CN107383173B true CN107383173B (en) | 2020-08-21 |
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| CN113711991A (en) * | 2020-11-02 | 2021-11-30 | 江门赛尔康生物科技有限公司 | Construction method and application of PAP (PAP) -targeted drug screening animal model |
| CN113455465B (en) * | 2021-06-29 | 2023-02-28 | 安徽省立医院(中国科学技术大学附属第一医院) | Method for constructing nude mouse subcutaneous transplantation model of human prostate cancer LNCaP cell |
| CN118121690A (en) * | 2024-01-29 | 2024-06-04 | 首都医科大学附属北京友谊医院 | Use of inhibitors of tyrosine phosphorylation of prostata specific acid phosphatase or/and ATG14 in prostate cancer |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1218833A (en) * | 1998-05-20 | 1999-06-09 | 北京医科大学 | Polypeptide with cell withering promoting activity |
| CN1422333A (en) * | 2000-03-10 | 2003-06-04 | 中外制药株式会社 | Polypeptide inducing apoptosis |
-
2017
- 2017-08-07 CN CN201710667184.0A patent/CN107383173B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1218833A (en) * | 1998-05-20 | 1999-06-09 | 北京医科大学 | Polypeptide with cell withering promoting activity |
| CN1422333A (en) * | 2000-03-10 | 2003-06-04 | 中外制药株式会社 | Polypeptide inducing apoptosis |
Non-Patent Citations (1)
| Title |
|---|
| 《Beclin1 进化保守区-SA融合蛋白偶联生物素-A10适配子制备PSMA靶向系统及其对前列腺癌细胞的抑制》;高萌等;《中国肿瘤生物治疗杂志》;20160430;第23卷(第2期);第161-167页 * |
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