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2016 ; 36
(20
): 2626-44
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Differences and Similarities in TRAIL- and Tumor Necrosis Factor-Mediated
Necroptotic Signaling in Cancer Cells
#MMPMID27528614
Sosna J
; Philipp S
; Fuchslocher Chico J
; Saggau C
; Fritsch J
; Föll A
; Plenge J
; Arenz C
; Pinkert T
; Kalthoff H
; Trauzold A
; Schmitz I
; Schütze S
; Adam D
Mol Cell Biol
2016[Oct]; 36
(20
): 2626-44
PMID27528614
show ga
Recently, a type of regulated necrosis (RN) called necroptosis was identified to
be involved in many pathophysiological processes and emerged as an alternative
method to eliminate cancer cells. However, only a few studies have elucidated
components of TRAIL-mediated necroptosis useful for anticancer therapy.
Therefore, we have compared this type of cell death to tumor necrosis factor
(TNF)-mediated necroptosis and found similar signaling through acid and neutral
sphingomyelinases, the mitochondrial serine protease HtrA2/Omi, Atg5, and
vacuolar H(+)-ATPase. Notably, executive mechanisms of both TRAIL- and
TNF-mediated necroptosis are independent of poly(ADP-ribose) polymerase 1
(PARP-1), and depletion of p38? increases the levels of both types of cell death.
Moreover, we found differences in signaling between TNF- and TRAIL-mediated
necroptosis, e.g., a lack of involvement of ubiquitin carboxyl hydrolase L1
(UCH-L1) and Atg16L1 in executive mechanisms of TRAIL-mediated necroptosis.
Furthermore, we discovered indications of an altered involvement of mitochondrial
components, since overexpression of the mitochondrial protein Bcl-2 protected
Jurkat cells from TRAIL- and TNF-mediated necroptosis, and overexpression of
Bcl-XL diminished only TRAIL-induced necroptosis in Colo357 cells. Furthermore,
TRAIL does not require receptor internalization and endosome-lysosome
acidification to mediate necroptosis. Taken together, pathways described for
TRAIL-mediated necroptosis and differences from those for TNF-mediated
necroptosis might be unique targets to increase or modify necroptotic signaling
and eliminate tumor cells more specifically in future anticancer approaches.
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