Pseurotin A Validation as a Metastatic Castration-Resistant Prostate Cancer Recurrence-Suppressing Lead via PCSK9-LDLR Axis Modulation.
Pseurotin A Validation as a Metastatic Castration-Resistant Prostate Cancer Recurrence-Suppressing Lead via PCSK9-LDLR Axis Modulation.
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转移性去势耐受前列腺癌(MCRPC)细胞可以重新合成自身的胆固醇，并过表达原蛋白转换酶枯草杆菌/可信9(PCSK9)。PCSK9在mCRPC CWR-R1ca细胞中的敲除(KD)导致细胞迁移和集落形成显著减少，因此PCSK9被证明有助于mCRPC细胞的运动。人体组织芯片结果表明，65岁的≥患者具有较高的免疫组织核心，并且PCSK9在早期的Gleason评分为≤7时有较高的表达。发酵产物伪黄素A(PS)抑制了PCSK9的表达，抑制了与LDLR的蛋白质-蛋白质相互作用，并抑制了乳腺癌和前列腺癌的复发。PS抑制CWR-R1ca细胞的迁移和集落形成。CWR-R1ca-Luc细胞皮下移植到高脂饮食(HFD，11%脂肪含量)的雄性裸鼠体内的进展和转移显示，与常规饮食喂养的小鼠相比，肿瘤体积、转移率、血清胆固醇、低密度脂蛋白胆固醇(LDL-C)、前列腺特异性抗原(PSA)和PCSK9水平增加了近2倍。每日口服PS10 mg/kg可预防CWR-R1ca-Luc裸鼠初次肿瘤切除后局部和远处肿瘤复发。PS组小鼠的血清胆固醇、低密度脂蛋白-C、PCSK9和PSA水平显著降低。这些结果通过调节PCSK9-LDLR轴，全面验证了PS作为mCRPC复发抑制导联的作用。
Metastatic castration-resistant prostate cancer (mCRPC) cells can de novo biosynthesize their own cholesterol and overexpress proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 proved to contribute to mCRPC cell motility since PCSK9 knockdown (KD) in mCRPC CWR-R1ca cells led to notable reductions in cell migration and colony formation. Human tissue microarray results proved a higher immunohistoscore in patients ≥ 65 years old, and PCSK9 proved to be expressed higher at an early Gleason score of ≤7. The fermentation product pseurotin A (PS) suppressed PCSK9 expression, protein–protein interactions with LDLR, and breast and prostate cancer recurrences. PS suppressed migration and colony formation of the CWR-R1ca cells. The progression and metastasis of the CWR-R1ca-Luc cells subcutaneously (sc) xenografted into male nude mice fed a high-fat diet (HFD, 11% fat content) showed nearly 2-fold tumor volume, metastasis, serum cholesterol, low-density lipoprotein cholesterol (LDL-C), prostate-specific antigen (PSA), and PCSK9 levels versus mice fed a regular chow diet. Daily oral PS 10 mg/kg treatments prevented the locoregional and distant tumor recurrence of CWR-R1ca-Luc engrafted into nude mice after primary tumor surgical excision. PS-treated mice showed a significant reduction in serum cholesterol, LDL-C, PCSK9, and PSA levels. These results comprehensively validate PS as an mCRPC recurrence-suppressive lead by modulating the PCSK9-LDLR axis.
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DOI：
10.1158/1055-9965.epi-18-0812
发表时间：
2019-03
期刊：
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
影响因子：
--
作者：
Awasthi S;Gerke T;Park JY;Asamoah FA;Williams VL;Fink AK;Balkrishnan R;Lee DI;Malkowicz SB;Lal P;Dhillon J;Pow-Sang JM;Rebbeck TR;Yamoah K
通讯作者：
Yamoah K
影响因子：
1.2
作者：
Clark, Aaron J.;Fakurnejad, Shayan;Hashizume, Rintaro
通讯作者：
Hashizume, Rintaro
影响因子：
5.1
作者：
Lee, Ming-Shian;Wang, Shih-Wei;Lee, Tzong-Huei
通讯作者：
Lee, Tzong-Huei
影响因子：
2.8
作者：
Litvinov, Ivan V.;Antony, Lizamma;Isaacs, John T.
通讯作者：
Isaacs, John T.
影响因子：
56.9
作者：
BROWN, MS;GOLDSTEIN, JL
通讯作者：
GOLDSTEIN, JL