This time we are going to do a guest blogging with our partners of the ELISaassays
(www.elisaassays.com) and Molecutools (www.molecutools.com) companies, who will talk about inhibitor
of apoptosis protein sor IAPs as a fundamental components involved in tumoral
growth and development, as well as in chemotherapy resistance. In the same way,
they have published in the ELISAassays blog our post about migraines. This kind of online
colaboration is a great way to spread and divulge knowledge in some respects.
We hope to be the first
of many collaborations!
Tumours develop due to rapid proliferation, decreased cell death, or the
combination of both factors. In most cases tumour cells do not have the chance
to develop due to the elimination of these cells by the induction of apoptosis
or programmed cell death, but sometimes the tumour can become resistant to
this effect. Resistance to apoptotic stimuli is a hallmark feature of various
cancers. Defects in apoptotic mechanisms also play an important role in
resistance to chemotherapy and radiation and have been implicated in the
acceleration of tumour progression and metastasis (Thompson, 1995). One
mechanism of resistance to apoptotic stimuli involves the over-expression of
the inhibitor of apoposis proteins or IAPs. Clearly, the up-regulation
of IAP family members would be advantageous for tumours (Nachmias et al.,
2004).
Studies using biopsy material from cancer patients indicate a direct
association between IAP expression levels and the malignancy of individual
tumours. High expression of XIAP (X-linked inhibitor of apoptosis
protein), a concrete IAP also called IAP3, has been reported in many malignant
tumour types, such as carcinomas of the breast, ovaries, lung (Gerhard et
al., 2002), pancreas, cervix (Liu et al., 2001) and prostate, as
well as leukaemia (Tamm et al., 2000). High levels of XIAP have been
detected in primary cells of Hodgkin’s disease (HD), a kind of malignant
linfoma. The malignant Hodgkin and Reed Sternberg cells (HR-S) of Hodgkin
Lymphoma (HL) and HL-derived B cell lines had previously been shown to be
resistant to different apoptotic stimuli. Kashkar et al observed in 2003
that XIAP is expressed constitutively and at high levels in HL-derived B cells
as well as in HR-S cells of tumour biopsies. In addition, they detected that
cytochrome C, as well as caspase-8 or granzyme B-induced activation of caspase 3 is
severely impaired in lysates of HL-derived B cell lines. Functional
neutralisation of XIAP by the inhibitor Smac/DIABLO restored the apoptotic
response in both lysates and intact HL-derived B cells, suggesting that XIAP is
a main mediator of apoptotic resistance in HL (Kashkar et al., 2003).
XIAP structure (https://www.rcsb.org/pdb/)
A study carried out by Yan et al in 2004 in renal cell carcinomas
(RCCs) to explore the relevance and function of XIAP and Smac/DIABLO in tumour
progression revealed that XIAP and Smac/DIABLO mRNA expression was found in all
RCCs. Significantly, XIAP mRNA expression levels considerably increased from
early to advanced tumour stages and also with tumour differentiation. In
contrast mRNA and protein expression levels of Smac/DIABLO did not
significantly alter between high and low tumour grades. This investigation
demonstrated for the first time a stage and grade-dependent increase of
anti-apoptotic XIAP expression in human RCCs. The balance between XIAP and
Smac/DIABLO expression is gradually disturbed during progression of RCC,
possibly contributing to the resistance to apoptosis in RCCs (Yan et al.,
2004).
www.ourbodiesourselves.org
Concluding, these studies show the role XIAP plays in tumour development
and progression. IAPs appear to be crucial in keeping the tumour cells alive
and triggering resistance to chemotherapeutic drugs. Thus understanding the
biological role of these inhibitors will facilitate the design of more
efficient and selective drugs that could overcome apoptosis resistance in
certain cell types.
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