Prostate cell differentiation status determines transient receptor potential melastatin member 8 channel subcellular localization and function.
In recent years, the transient receptor potential melastatin member 8 (TRPM8) channel has emerged as a promising prognostic marker and putative therapeutic target in prostate cancer (PCa). However, the mechanisms of prostate-specific regulation and functional evolution of TRPM8 during PCa progression remain unclear. Here we show, for the first time to our knowledge, that only secretory mature differentiated human prostate primary epithelial (PrPE) luminal cells expressed functional plasma membrane TRPM8 ((PM)TRPM8) channels. Moreover, PCa epithelial cells obtained from in situ PCa were characterized by a significantly stronger (PM)TRPM8-mediated current than that in normal cells. This (PM)TRPM8 activity was abolished in dedifferentiated PrPE cells that had lost their luminal secretory phenotype. However, we found that in contrast to (PM)TRPM8, endoplasmic reticulum TRPM8 ((ER)TRPM8) retained its function as an ER Ca(2+) release channel, independent of cell differentiation. We hypothesize that the constitutive activity of (ER)TRPM8 may result from the expression of a truncated TRPM8 splice variant. Our study provides insight into the role of TRPM8 in PCa progression and suggests that TRPM8 is a potentially attractive target for therapeutic intervention: specific inhibition of either (ER)TRPM8 or (PM)TRPM8 may be useful, depending on the stage and androgen sensitivity of the targeted PCa.
Bidaux
Gabriel
G
INSERM U800, Equipe labellisée par la Ligue Nationale Contre le Cancer, Villeneuve d'Ascq, France.
Flourakis
Matthieu
M
Thebault
Stéphanie
S
Zholos
Alexander
A
Beck
Benjamin
B
Gkika
Dimitra
D
Roudbaraki
Morad
M
Bonnal
Jean-Louis
JL
Mauroy
Brigitte
B
Shuba
Yaroslav
Y
Skryma
Roman
R
Prevarskaya
Natalia
N
D017398:Alternative Splicing; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008297:Male; D011467:Prostate / Q000166:cytology* / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D013347:Subcellular Fractions / Q000378:metabolism; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*
D014408:Biomarkers, Tumor; D020033:Protein Isoforms; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human