Differential receptor dependencies: expression and significance of muscarinic M1 receptors in the biology of prostate cancer.
Recent reports on acetylcholine muscarinic receptor subtype 3 (CHRM3) have shown its growth-promoting role in prostate cancer. Additional studies report the proliferative effect of the cholinergic agonist carbachol on prostate cancer by its agonistic action on CHRM3. This study shows that the type 1 acetylcholine muscarinic receptor (CHRM1) contributes toward the proliferation and growth of prostate cancer. We used growth and cytotoxic assays, the prostate cancer microarray database and CHRM downstream pathways' homology of CHRM subtypes to uncover multiple signals leading to the growth of prostate cancer. Growth assays showed that pilocarpine stimulates the proliferation of prostate cancer. Moreover, it shows that carbachol exerts an additional agonistic action on nicotinic cholinergic receptor of prostate cancer cells that can be blocked by tubocurarine. With the use of selective CHRM1 antagonists such as pirenzepine and dicyclomine, a considerable inhibition of proliferation of prostate cancer cell lines was observed in dose ranging from 15-60 µg/ml of dicyclomine. The microarray database of prostate cancer shows a dominant expression of CHRM1 in prostate cancer compared with other cholinergic subtypes. The bioinformatics of prostate cancer and CHRM pathways show that the downstream signalling include PIP3-AKT-CaM-mediated growth in LNCaP and PC3 cells. Our study suggests that antagonism of CHRM1 may be a potential therapeutic target against prostate cancer.
aDepartment of Biological and Biomedical Sciences, Aga Khan University bDepartment of Surgery, Aga Khan University Hospital, Karachi, Pakistan cDepartment of Biological Sciences, Faculty of Science and Technology, Sunway University, Subang Jaya, Malaysia.
Abdul
A
Mannan Baig
Naveed A
NA
Khan
Vardah
V
Effendi
Zohaib
Z
Rana
H R
HR
Ahmad
Farhat
F
Abbas
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D004025:Dicyclomine / Q000494:pharmacology; D006801:Humans; D008297:Male; D010890:Pirenzepine / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043643:Receptor, Muscarinic M1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D043587:Receptor, Muscarinic M3 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction
C410798:AR protein, human; C086088:CHRM1 protein, human; C000595896:CHRM3 protein, human; D043643:Receptor, Muscarinic M1; D043587:Receptor, Muscarinic M3; D011944:Receptors, Androgen; D010890:Pirenzepine; D004025:Dicyclomine; D051057:Proto-Oncogene Proteins c-akt