HealthValue
HEAT SHOCK PROTEINS AND CANCER
HSPs are a group of proteins whose expression is increased when cells are exposed to elevated temperature or other forms of "stress" (infection, inflammation, hypoxia). HSPs represent 2 to 6 % of cell proteins. The 3 essential HSPs are HSP 90, HSP 70 and HSP 27.
Their main common functions are :
- Chaperone activity by which they participate in the folding of "client" proteins, such as tyrosine-kinases, serine-threonine kinases (and in particular PKB/AKT pathway kinases), hormone receptors.
- Inhibition of apoptosis.
- Activation of proteasomes & NFkappaB pathway.
HSPs are present in most cellular compartments :
- membrane
- cytosol,
- endoplasmic reticulum
- nucleus,
- mitochondrial membrane.
Proteasome
Cell
membrane
Mitochondria
Nucleus
Endoplasmic
reticulum
Cytosol
HSP 27
- inhibited by OGX-427
Induction of VEGF and
Matrix metalloproteinase
(facilitates metastasis)
HSP 90 overexpressed in breast cancer
- Inhibited by alvespimycin, fom Novartis AUY922 & HSP990; UDC 305, CNF1010, CNF2024, IPI 504 (retaspimycin).
HSP 70
- overexpressed in melanoma & BC
Binds protein fragments from dead cancer cells, & brings them to APCs, then plays a role in migration of APCs to lymph nodes. This can explain auto-immune sequelae.
Abbreviations : APC antigen presenting cells; BC breast cancer; RCC renal cell cancer
MONOCLONALS
DISEASES
Pathways
ABOUT MONOCLONALS
BioTherapies
Cells/organelles
STA4783, disappointing later, had shown remarkable phase 2 results on PFS (progression free survival) in metastatic melanoma. This might or might very well not be linked only to its activity on HSP70. Elesclomol also increases the level of reactive oxygen species, and of caspase induced apoptosis). Many other mechanisms are being explored. Increase in HSP 70 inhibits NFkB, which is highly carcinogenic.
This is a bit like for the discovery of Fleming, activity discovered before the mode of action is clear. IT CAN BE MISLEADING.
