Home > Apoptosis in Multiple Myeloma
What is apoptosis?
Apoptosis is a regulated cell death process that occurs under physiological and pathological conditions
and results from the activation of caspases (members of cysteine protease family that are responsible
for activation of cellular proteases and endonucleases). Apoptosis is executed through two main
pathways: the death receptor (DR) pathway and the mitochondrial pathway. The DR pathway is activated by
ligation of members of the tumor necrosis factor (TNF) family to DR on the plasma membrane triggering
caspase activation. In contrast, the mitochondrial pathway is regulated primarily by members of the
Bcl-2 family, which includes both pro-apoptotic and anti-apoptotic proteins. The ratio between pro- and
anti-apoptotic proteins determines susceptibility of cells to death signals.46
Apoptosis is avoided by myeloma cells through a number of mechanisms. High proteasome activity prevents
the unfolded protein response from activating
apoptosis.42,47 Interactions with the bone marrow stromal cells induce the
secretion of cytokines and growth factors. These interactions lead to the activation of NF-kB and
Notch-1, as well as the secretion of soluble factors such as TNF-a, TGF-β, lL-1β, bFGF, VEGF,
and IL-6. Increased levels of expression of Bcl-2, Bcl-xL, and Mcl-1 have been linked to multiple
myeloma cell survival and resistance to chemotherapeutic agents. In multiple myeloma there is higher
expression of the anti-apoptotic factors Bcl-2 and Mcl-1 but not of Bcl-xL, and there is a lower level
of
expression of Bax.46 The figure shows that by shifting the balance toward
anti-apoptotic Bcl-2, Bcl-xl, and Mcl-1, and away from pro-apoptotic factors Bax, Bak, Bid, Bcl-xS, Bad,
Bik, Puma, Noxa, and Hrk, myeloma cells avoid caspase activation and apoptosis.46-48
The apoptotic pathway leading to cell death48-51
Abbreviations
- TNF-α
- Tumor necrosis factor alpha
- TGF-β
- Transforming growth factor beta
- IL-1β
- Interleukin-1 beta
- bFGF
- Basic fibroblast growth factor
- VEGF
- Vascular endothelial growth factor
- IL-6
- Interleukin-6
- Bcl-2
- B-cell lymphoma 2
- Bcl-xL
- B-cell lymphoma-extra large
- Mcl-1
- Myeloid cell leukemia 1
- Bax
- Bcl-2-associated X
- Bak
- Bcl-2 homologous antagonist killer
- Bid
- BH3 interacting-domain death agonist
- Bcl-xS
- B-cell lymphoma-extra short
- Bad
- Bcl-2-associated death promoter
- Bik
- Bcl-2-interacting killer
- Puma
- p53 upregulated modulator of apoptosis
- Noxa
- Phorbol-12-myristate-13-acetate-induced protein 1
- Hrk
- Activator of apoptosis harakiri