Book of abstract 2008

The role of the immune proteasomes in the anticancer defence
N. P. Sharova1 , T. M. Astakhova1, L. A. Zakharova1, Ya. D. Karpova1, I. I. Khegay2
1N. K. Koltsov Institute of Developmental Biology, Russian Academy of Sciences, Moscow; 2Institute of
cytology and genetics, Sibirian Dept. of Russian Academy of Sciences, Novosibirsk
The immune proteasomes play an important role in the mammalian and human T cell
immunity. Producing the antigenic epitops from proteins, they participate in the negative
selection of thymocytes in thymus and in the activation of naive T-CD8+ lymphocytes in
the secondary lymphoid organs. In any tissue or organ except the brain, the immune proteasomes
switch on the signal for the elimination of abnormal cells which express altered
(mutant) or foreign (viral) genes. In such cells the immune proteasomes produce or start
the production of antigenic epitops from mutant or viral proteins. An antigenic epitop
binds molecules of the major histocompatibility complex class I to be transported to the
cell surface. This structure represents the signal for cytotoxic T lymphocytes to identify
abnormal cells and induce their apoptosis. On the one hand, if the immune system is defective,
numerous mutations in somatic cells can cause the malignant transformation. On
the other hand, can changes in the immune proteasome pool in a cell be related to its
malignant transformation? To answer this question, we investigated the peculiarities of
the immune proteasome pool in the developed ascite carcinoma Krebs-II on the 7 th day
after transplanting to Balb/c mice. Besides, we investigated the changes in the immune
proteasome pools in carcinosarcoma Walker 256 on the 7 th and 14 th days after transplanting
to WAG and Brattleboro rats. The latter are the unique vasopressin deficient rats in
which malignant tumor Walker 256 slowly grows up to the 15-18 th day, then decreases and
disappears up to the 30 th day. In all experiments, we compared the changes in the immune
proteasome pool with those of the total proteasome pool and 26S-proteasome pool by
Western blotting.
We showed that the level of the immune proteasomes in all developing tumors dra-matically
falls. Besides, proteasome pool is deficient in the immune subtypes in Walker 256 cells
in Brattleboro rats on 7 th day, and on the contrary, the level of the immune proteasomes
significantly increases in this tumor up to 14
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th day. These data confirm that the reason of
the successful development of a malignant tumor may be related to the partial or complete
exclusion of the immune proteasomes from its cells. That allows these cells to avoid the
immune surveillance. In contrast to the growing tumor, the in-crease of the immune proteasome
level in the disappearing tumor may open its cells to the immune system and it
can be the reason of the tumor regression. It is interesting that the decrease of the immune
proteasome level in the growing tumors is accompanied by the increase of the 26S-proteasome
pool and of the total proteasome pool levels, and on the contrary, the increase of the
immune proteasome level in the regressing tumor is ac-companied by the decrease of the
total proteasome pool level. Moreover, in the cells of regressing tumor in Brattleboro rats,
26S-proteasomes disappear at all up to the 14 th day. It is clear that increased pool of 26S
proteasomes is necessary for exact cell cycle regulation of actively proliferating tumor cells
and its elimination can be the second reason of the tumor regression. Thus, the peculiarities
of the proteasome expression in tumor cells define their future fate.
Supported by the Russian Foundation for Basic Research (projects 05-04-48830 and 06-04-48229).
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