Curcumin Targets Breast Cancer Stem–like Cells with Microtentacles That Persist in Mammospheres and Promote Reattachment

Abstract

Cancer stem-like cells (CSC) and circulating tumor cells (CTCs) have related properties associated with distant metastasis, but the mechanisms through which CSCs promote metastasis are unclear. In this study, we report that breast cancer cell lines with more stem-like properties display higher levels of microtentacles (McTNs), a type of tubulin-based protrusion of the plasma cell membrane which forms on detached or suspended cells and aid in cell reattachment. We hypothesized that CSCs with large numbers of McTNs would more efficiently attach to distant tissues, promoting metastatic efficiency. The naturally occurring stem-like subpopulation of the HMLE breast cell line presents increased McTNs compared to its isogenic non-stem-like subpopulation. This increase was supported by elevated α-tubulin detyrosination and vimentin protein levels and organization. Increased McTNs in stem-like HMLEs promoted a faster initial reattachment of suspended cells that was inhibited by the tubulin-directed drug, colchicine, confirming a functional role for McTN in stem cell reattachment. Moreover, live cell confocal microscopy showed that McTN persist in breast stem cell mammospheres as flexible, motile protrusions on the surface of the mammosphere. While exposed to the environment, they also function as extensions between adjacent cells along cell-cell junctions. We found that treatment with the breast CSC-targeting compound curcumin rapidly extinguished McTN in breast CSC, preventing reattachment from suspension. Together, our results support a model in which breast CSCs with cytoskeletal alterations that promote McTN can mediate attachment and metastasis but might be targeted by curcumin as an anti-metastatic strategy.

ROCK inhibition promotes microtentacles that enhance reattachment of breast cancer cells

“…But at the same time, it also calls to attention the possible implications of using ROCK inhibitors as cancer therapeutics if they promote survival and possibly conversion of detached tumor cells towards a stem-like phenotype. We have recently reported that breast cancer cell lines with higher stem-like characteristics have increased McTNs that promote their reattachment from suspension [57]. These findings indicate that chemotherapeutics that inadvertently promote such stem-like characteristics might be detrimental to overall progression-free survival.…”

Targeting the Cytoskeleton with Plant-Bioactive Compounds in Cancer Therapy

“…It is severely toxic to normal tissues at high dose, which limits its use in cancer therapies [19]. Colchicine showed diferent antitumoral efects which include inhibition of metastatic potential [20] and angiogenesis [21], cell blebbing through a Rho/Rho efector kinase (ROCK)/ myosin light-chain kinase (MLCK) pathway [22], decrease of ATP inlux into mitochondria [23].…”

Chemoprevention in Gastrointestinal Physiology and Disease. Natural products and microbiome

“…Interestingly, it was found that curcumin could inhibit mammosphere formation and could also decrease the amount of aldehyde dehydrogenase-positive cells in normal and malignant breast cancer cells through the inhibition of Wnt signaling (23), suggesting the inhibitory effects of curcumin on breast cancer stem cells (23). Curcumin has also been found to inhibit the expression of several molecules in Wnt/␤-catenin pathway including disheveled, ␤-catenin, cyclin D1, and slug in both MCF-7 and MDA-MB-231 breast cancer cells (23). Immunofluorescence staining showed that curcumin significantly reduced the nuclear expression of disheveled and ␤-catenin proteins.…”