HYD1-induced increase in reactive oxygen species leads to autophagy and necrotic cell death in multiple myeloma cells.
HYD1 is a D-amino acid peptide that was previously shown to inhibit adhesion of prostate cancer cells to the extracellular matrix. In this study, we show that in addition to inhibiting adhesion of multiple myeloma (MM) cells to fibronectin, HYD1 induces cell death in MM cells as a single agent. HYD1-induced cell death was necrotic in nature as shown by: (a) decrease in mitochondrial membrane potential (Deltapsi(m)), (b) loss of total cellular ATP, and (c) increase in reactive oxygen species (ROS) production. Moreover, HYD1 treatment does not result in apoptotic cell death because it did not trigger the activation of caspases or the release of apoptosis-inducing factor and endonuclease G from the mitochondria, nor did it induce double-stranded DNA breaks. HYD1 did initiate autophagy in cells; however, autophagy was found to be an adaptive response contributing to cell survival rather than the cause of cell death. We were further able to show that N-acetyl-L-cysteine, a thiol-containing free radical scavenger, partially protects MM cells from HYD1-induced death. Additionally, N-acetyl-L-cysteine blocked HYD1-induced as well as basal levels of autophagy, suggesting that ROS can potentially trigger both cell death and cell survival pathways. Taken together, our data describe an important role of ROS in HYD1-induced necrotic cell death in MM cells.
Nair
Rajesh R
RR
Moffitt Cancer Center, Tampa, Florida 33613, USA.
Emmons
Michael F
MF
Cress
Anne E
AE
Argilagos
Raul F
RF
Lam
Kit
K
Kerr
William T
WT
Wang
Hong-Gong
HG
Dalton
William S
WS
Hazlehurst
Lori A
LA
D000818:Animals; D001343:Autophagy; D016923:Cell Death; D045744:Cell Line, Tumor; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008854:Microscopy, Electron; D009101:Multiple Myeloma / Q000473:pathology*; D009336:Necrosis / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*
D009842:Oligopeptides; D010455:Peptides; D017382:Reactive Oxygen Species; C546443:lysyl-isoleucyl-lysyl-methionyl-valyl-isoleucyl-seryl-tryptophyl-lysyl-glycine