The Mechanosensory Ca2+ Channel as a Central Regulator of Prostate Tumor Cell Migration and Invasiveness
Annual rept. 18 Dec 2006-17 Dec 2007
TEXAS UNIV MEDICAL BRANCH AT GALVESTON
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Our patch clamp studies indicate MscCa is expressed by the invasive prostate tumor cell PC-3. Anti-MscCa agents, Gd3, GsmTx-4, and an anti-TRPC1 antibody block PC-3 cell migration. MscCa activity can be recorded over the surface of the PC-3 cell but is expressed at higher density on the rear compared with the front of the cell. This channel density gradient combined with a higher density of thapsigargin-sensitive Ca2 stores in the rear of the cell enables the development of an intracellular Ca2 gradient low front high rear in migrating PC- 3 cells that determines migration directionality. Gene silencing of TRPC1 andor TRPC3, but not TRPC4 or TRPC6, blocks PC-3 cell migration. Permanently suppressing TRPC1 also reduces PC-3 cell proliferation and thereby blocks tumor invasion in vivo. The noninvasive human prostate tumor cell line LNCaP expresses MscCa but the channel undergoes rapid inactivation that prevents Ca2 gradient development and directional cell migration. Our results indicate that specific forms of mechanical stimuli can switch the inactivating gating mode to the non-inactivating mode seen in PC-3 cells, and this switch is independent of the actin-cytoskeleton. These findings have specific implications regarding the possible role of the increases mechanical forces e.g., solid stress and interstitial fluid compression that develop within a growing prostate tumor in promoting its progression to malignancy.
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