The mechanisms of the anti-tumour effect of inactivating ICMT in BRAF-induced cancer

Abstract

B-Raf, an important component of the Mitogen-Activated Protein Kinase (MAPK) pathway, has been shown to be mutated in 66% of malignant melanomas as well as other types of cancer leading to hyper-activation of the MAPK pathway. B-RAF inhibitors have been introduced as potential therapy treatments for these cancer patients, showing promising initial results but a resistance to the drug is soon formed and the disease progresses. This has turned research towards other potential therapeutic targets such as the enzyme Isoprenylcysteine carboxyl methyltransferase (ICMT) which has been shown to reduce the growth of both KRAS and BRAF induced cancers by means which are still not fully understood. Previous work in our group has shown ICMT knockouts to accumulate an age related protein, Prelamin A, in their nuclear membrane. Through use of Cre/Lox technology we show in vitro that Prelamin A accumulation mediates the effect ICMT inhibition has on BRAF transformed cells. Our results also show that knocking out ICMT abolishes the PI3K/Akt pathway downstream of KRAS in transformed cells however the MAPK pathway is unaffected and remains constitutively active. Thus, by inhibiting ICMT we seem to be able to induce premature senescence in transformed cancer cells by accumulating the precursor protein; Prelamin A and by down-regulating the PI3k/Akt pathway.