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TRAIL signaling promotes entosis in colorectal cancer.

ABSTRACT: Entosis is a form of nonphagocytic cell-in-cell (CIC) interaction where a living cell enters into another. Tumors show evidence of entosis; however, factors controlling entosis remain to be elucidated. Here, we find that besides inducing apoptosis, TRAIL signaling is a potent activator of entosis in colon cancer cells. Initiation of both apoptosis and entosis requires TRAIL receptors DR4 and DR5; however, induction of apoptosis and entosis diverges at caspase-8 as its structural presence is sufficient for induction of entosis but not apoptosis. Although apoptosis and entosis are morphologically and biochemically distinct, knockout of Bax and Bak, or inhibition of caspases, also inhibits entotic cell death and promotes survival and release of inner cells. Analysis of colorectal cancer tumors reveals a significant association between TRAIL signaling and CIC structures. Finally, the presence of CIC structures in the invasive front regions of colorectal tumors shows a strong correlation with adverse patient prognosis.

SUBMITTER: Bozkurt E

PROVIDER: S-EPMC8563286 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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TRAIL signaling promotes entosis in colorectal cancer.

Bozkurt Emir E Düssmann Heiko H Salvucci Manuela M Cavanagh Brenton L BL Van Schaeybroeck Sandra S Longley Daniel B DB Martin Seamus J SJ Prehn Jochen H M JHM

The Journal of cell biology 20210921 11

Entosis is a form of nonphagocytic cell-in-cell (CIC) interaction where a living cell enters into another. Tumors show evidence of entosis; however, factors controlling entosis remain to be elucidated. Here, we find that besides inducing apoptosis, TRAIL signaling is a potent activator of entosis in colon cancer cells. Initiation of both apoptosis and entosis requires TRAIL receptors DR4 and DR5; however, induction of apoptosis and entosis diverges at caspase-8 as its structural presence is suff ...[more]

PMID: 34546352

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Project description:BackgroundColorectal cancer (CRC) is characterized by a pro-inflammatory microenvironment and features high-energy-supply molecules that assure tumor growth. A still less studied macromolecule is inorganic polyphosphate (iPolyP), a high-energy linear polymer that is ubiquitous in all forms of life. Made up of hundreds of repeated orthophosphate units, iPolyP is essential for a wide variety of functions in mammalian cells, including the regulation of proliferative signaling pathways. Some evidence has suggested its involvement in carcinogenesis, although more studies need to be pursued. Moreover, iPolyP regulates several homeostatic processes in animals, spanning from energy metabolism to blood coagulation and tissue regeneration.ResultsIn this study, we tested the role of iPolyP on CRC proliferation, using in vitro and ex vivo approaches, in order to evaluate its effect on tumor growth. We found that iPolyP is significantly increased in tumor tissues, derived from affected individuals enrolled in this study, compared to the corresponding peritumoral counterparts. In addition, iPolyP signaling occurs through the TRPM8 receptor, a well-characterized Na+ and Ca2+ ion channel often overexpressed in CRC and linked with poor prognosis, thus promoting CRC cell proliferation. The pharmacological inhibition of TRPM8 or RNA interference experiments performed in established CRC cell lines, such as Caco-2 and SW620, showed that the involvement of TRPM8 is essential, greater than that of the other two known iPolyP receptors, P2Y1 and RAGE. The presence of iPolyP drives cancer cells towards the mitotic phase of the cell cycle by enhancing the expression of ccnb1, which encodes the Cyclin B protein. In vitro 2D and 3D data reflected the ex vivo results, obtained by the generation of CRC-derived organoids, which increased in size.ConclusionsThese results indicate that iPolyP may be considered a novel and unexpected early biomarker supporting colorectal cancer cell proliferation.

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TRAIL signaling promotes entosis in colorectal cancer.

Publications

TRAIL signaling promotes entosis in colorectal cancer.

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