PMID- 37103355
OWN - NLM
STAT- MEDLINE
DCOM- 20230501
LR  - 20230501
IS  - 1660-3397 (Electronic)
IS  - 1660-3397 (Linking)
VI  - 21
IP  - 4
DP  - 2023 Mar 28
TI  - Pseurotin A Validation as a Metastatic Castration-Resistant Prostate Cancer 
      Recurrence-Suppressing Lead via PCSK9-LDLR Axis Modulation.
LID - 10.3390/md21040215 [doi]
LID - 215
AB  - 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.
FAU - Abdelwahed, Khaldoun S
AU  - Abdelwahed KS
AD  - School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, 
      University of Louisiana at Monroe, Monroe, LA 71201, USA.
FAU - Siddique, Abu Bakar
AU  - Siddique AB
AD  - School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, 
      University of Louisiana at Monroe, Monroe, LA 71201, USA.
FAU - Ebrahim, Hassan Y
AU  - Ebrahim HY
AUID- ORCID: 0000-0001-9057-4582
AD  - School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, 
      University of Louisiana at Monroe, Monroe, LA 71201, USA.
FAU - Qusa, Mohammed H
AU  - Qusa MH
AD  - School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, 
      University of Louisiana at Monroe, Monroe, LA 71201, USA.
FAU - Mudhish, Ethar A
AU  - Mudhish EA
AUID- ORCID: 0000-0003-3677-6575
AD  - School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, 
      University of Louisiana at Monroe, Monroe, LA 71201, USA.
FAU - Rad, Ashkan H
AU  - Rad AH
AUID- ORCID: 0000-0002-5748-4160
AD  - School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, 
      University of Louisiana at Monroe, Monroe, LA 71201, USA.
FAU - Zerfaoui, Mourad
AU  - Zerfaoui M
AD  - Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 
      70112, USA.
FAU - Abd Elmageed, Zakaria Y
AU  - Abd Elmageed ZY
AUID- ORCID: 0000-0003-4031-0348
AD  - Department of Biomedical Sciences, Discipline of Pharmacology, Edward Via College 
      of Osteopathic Medicine, University of Louisiana at Monroe, Monroe, LA 71203, 
      USA.
FAU - El Sayed, Khalid A
AU  - El Sayed KA
AUID- ORCID: 0000-0002-1456-4064
AD  - School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, 
      University of Louisiana at Monroe, Monroe, LA 71201, USA.
LA  - eng
GR  - R21CA263290/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20230328
PL  - Switzerland
TA  - Mar Drugs
JT  - Marine drugs
JID - 101213729
RN  - EC 3.4.21.- (PCSK9 protein, human)
RN  - EC 3.4.21.- (Proprotein Convertase 9)
RN  - 58523-30-1 (pseurotin)
RN  - EC 3.4.21.- (Serine Endopeptidases)
RN  - EC 3.4.21.- (Proprotein Convertases)
RN  - EC 3.4.21.77 (Prostate-Specific Antigen)
RN  - 0 (Receptors, LDL)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - EC 3.4.21.- (Pcsk9 protein, mouse)
SB  - IM
MH  - Humans
MH  - Male
MH  - Mice
MH  - Animals
MH  - Aged
MH  - *Proprotein Convertase 9/genetics/metabolism
MH  - Mice, Nude
MH  - *Prostatic Neoplasms, Castration-Resistant/drug therapy
MH  - Serine Endopeptidases/metabolism
MH  - Proprotein Convertases/metabolism
MH  - Prostate-Specific Antigen
MH  - Receptors, LDL/genetics/metabolism
MH  - Cholesterol
PMC - PMC10144979
OTO - NOTNLM
OT  - LDLR
OT  - PCSK9
OT  - castration-resistant prostate cancer
OT  - cholesterol
OT  - colony formation
OT  - fermentation
OT  - immunohistoscore
OT  - pseurotin A
OT  - recurrence
OT  - tissue microarray
COIS- K.A. El Sayed is a cofounder and equity shareholder for Oleolive, 
      Shreveport-Louisiana. The rest of the authors declare no conflicts of interest. 
      The funders had no role in the design of the study; in the collection, analyses, 
      or interpretation of data; in the writing of the manuscript; or in the decision 
      to publish the results.
EDAT- 2023/04/27 12:42
MHDA- 2023/05/01 06:42
PMCR- 2023/03/28
CRDT- 2023/04/27 10:53
PHST- 2023/02/27 00:00 [received]
PHST- 2023/03/22 00:00 [revised]
PHST- 2023/03/24 00:00 [accepted]
PHST- 2023/05/01 06:42 [medline]
PHST- 2023/04/27 12:42 [pubmed]
PHST- 2023/04/27 10:53 [entrez]
PHST- 2023/03/28 00:00 [pmc-release]
AID - md21040215 [pii]
AID - marinedrugs-21-00215 [pii]
AID - 10.3390/md21040215 [doi]
PST - epublish
SO  - Mar Drugs. 2023 Mar 28;21(4):215. doi: 10.3390/md21040215.