Biology Reference
In-Depth Information
located within tumor cells. Once inside tumor cells, NE degrades a novel target
substrate called insulin receptor substrate-1 (IRS-1). IRS-1 is a key regulator of the
phosphoinositol-3 kinase (PI3K) pathway, which dictates cell proliferation and
survival. Upon the degradation of IRS-1, the homeostatic binding partner of PI3K
is lost, and PI3K is subsequently free to bind to more potent growth factors, such as
the platelet-derived growth factor and receptor (PDGF and PDGFR). PI3K-PDGFR
interaction activates PI3K signaling, resulting in tumor cell proliferation. This
represents the first description of a secreted proteinase gaining access to another
cell and effecting its intracellular signaling. This concept greatly expands the list of
potential substrates and functions for secreted proteinases in cancer.
The protumor function of NE also translates to human disease. The inverse
relationship identified between NE and IRS-1 in murine tumors also exists in
human lung adenocarcinomas. In other words, the presence of NE infiltration in
human cancers correlates with absence of its target substrate, IRS-1. NE-inhibition
may prove to be a viable therapeutic option for human cancers, as treatment of
tumor-bearing mice with a synthetic NE antagonist, ONO-5046, reduced tumor
growth in vivo. Part of the failure of clinical trials employing MMP inhibitors as
cancer therapy stemmed from the varied prohost and protumor functions of the
different MMPs (Coussens et al.
2002
). One would not expect similar problems
using highly specific single agent therapy against NE as cancer chemotherapy.
9.7 Conclusions
Elastic fibers are unique and highly cross-linked structural proteins that evolved to
provide flexibility to tissues and to provide the required resiliency of blood vessels
in a closed circulatory system. The creation of a mature elastic fiber is a complex
temporal-spatial process involving numerous cell types and proteins that cannot be
adequately duplicated after the earliest stages of postnatal life. Elastases were
developed prior to elastin, as they appeared much earlier during the course of
evolution. Their ability to degrade elastin provides no apparent advantage to the
host. The ability to degrade elastin may serve as a “marker” of an extremely
effective enzyme with broad substrate specificity. Many of these enzymes perform
paramount functions in host defense, which explains why their side effect (elasto-
lysis) would be tolerated.
References
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Adair-Kirk TL, Atkinson JJ et al (2003) A site on laminin alpha 5, AQARSAASKVKVSMKF,
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