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Thorisson, B. (2011) Inactivation of isoprenylcysteine carboxyl methyltransferase reduces proliferation of BRAF and NRAS mutated human melanoma cells. Göteborg : Chalmers University of Technology
BibTeX
@mastersthesis{
Thorisson2011,
author={Thorisson, Bjarni},
title={Inactivation of isoprenylcysteine carboxyl methyltransferase reduces proliferation of BRAF and NRAS mutated human melanoma cells},
abstract={Malignt melanoma is the deadliest form of skin cancer, with an increasing incidence worldwide. Surgical removal of the tumors can be an effective first line of defense. Nonetheless, when the tumors have metastasized, the prognosis is extremely poor and not influenced by systematic therapy with cytotoxic drugs. The two most common mutations in malignant melanoma are <I>BRAF</I> and <I>NRAS</I>, with the prevalence of 47% and 21%, respectively. Newly developed selective inhibitors have shown profound clinical results in patients that carry the <I>BRAF</I><sup>V600E</sup> mutation. However, the patients develop secondary resistance and subsequent disease progression. Also, tumors caused by mutations of <I>NRAS</I> or other oncogenes are accelerated by the BRAF selective inhibitors. It is therefore of paramount importance to explore alternative or combinatorial therapies to mitigate the incurred resistance mechanism. Isoprenylcysteine carboxyl methyltransferase (ICMT), is an endoplasmic reticulum membrane protein that catalyzes post-translational carboxyl methylation of proteins encoding a C-terminal CAAX motif (C, cystein, A, aliphatic amino acids, X, any amino acid). CAAX proteins have proved important for the function of various cancer cells, and preclinical studies have shown that inactivation of ICMT might be a potential target for anticancer drugs.<p></p> In this study we evaluated the impact of inactivating <I>ICMT</I> in <I>BRAF</I> and <I>NRAS</I> mutated human melanoma cell lines, alone and in combination with <I>BRAF</I> inactivation and thereby determine if <I>ICMT</I> inactivation or co-inactivation of <I>ICMT</I> and <I>BRAF</I> would reduce the proliferative ability of these cells. By using lentiviruses expressing <I>ICMT</I>- and <I>BRAF</I>- specific short hairpin (sh) RNA, we knocked down expression of <I>ICMT</I> and <I>BRAF</I> independently and in combination in these mutated melanoma cell lines. <p></p>Inactivation of <I>ICMT</I> or <I>BRAF</I> alone significantly reduced the proliferation of <I>BRAF</I> and <I>NRAS</I> mutated human melanoma cell lines. The simultaneous inactivation of <I>ICMT</I> and <I>BRAF</I> resulted in a significant reduction of proliferation in these cells. However, the reduction did not exceed independent inactivation of <I>ICMT</I> or <I>BRAF</I>. These results indicate that targeting ICMT in human malignant melanoma could be an attractive strategy, which will be further explored.},
publisher={Institutionen för kemi- och bioteknik, Chalmers tekniska högskola},
place={Göteborg},
year={2011},
keywords={ICMT, BRAF, NRAS, human malignant melanoma},
note={21},
}
RefWorks
RT Generic
SR Electronic
ID 141685
A1 Thorisson, Bjarni
T1 Inactivation of isoprenylcysteine carboxyl methyltransferase reduces proliferation of BRAF and NRAS mutated human melanoma cells
YR 2011
AB Malignt melanoma is the deadliest form of skin cancer, with an increasing incidence worldwide. Surgical removal of the tumors can be an effective first line of defense. Nonetheless, when the tumors have metastasized, the prognosis is extremely poor and not influenced by systematic therapy with cytotoxic drugs. The two most common mutations in malignant melanoma are <I>BRAF</I> and <I>NRAS</I>, with the prevalence of 47% and 21%, respectively. Newly developed selective inhibitors have shown profound clinical results in patients that carry the <I>BRAF</I><sup>V600E</sup> mutation. However, the patients develop secondary resistance and subsequent disease progression. Also, tumors caused by mutations of <I>NRAS</I> or other oncogenes are accelerated by the BRAF selective inhibitors. It is therefore of paramount importance to explore alternative or combinatorial therapies to mitigate the incurred resistance mechanism. Isoprenylcysteine carboxyl methyltransferase (ICMT), is an endoplasmic reticulum membrane protein that catalyzes post-translational carboxyl methylation of proteins encoding a C-terminal CAAX motif (C, cystein, A, aliphatic amino acids, X, any amino acid). CAAX proteins have proved important for the function of various cancer cells, and preclinical studies have shown that inactivation of ICMT might be a potential target for anticancer drugs.<p></p> In this study we evaluated the impact of inactivating <I>ICMT</I> in <I>BRAF</I> and <I>NRAS</I> mutated human melanoma cell lines, alone and in combination with <I>BRAF</I> inactivation and thereby determine if <I>ICMT</I> inactivation or co-inactivation of <I>ICMT</I> and <I>BRAF</I> would reduce the proliferative ability of these cells. By using lentiviruses expressing <I>ICMT</I>- and <I>BRAF</I>- specific short hairpin (sh) RNA, we knocked down expression of <I>ICMT</I> and <I>BRAF</I> independently and in combination in these mutated melanoma cell lines. <p></p>Inactivation of <I>ICMT</I> or <I>BRAF</I> alone significantly reduced the proliferation of <I>BRAF</I> and <I>NRAS</I> mutated human melanoma cell lines. The simultaneous inactivation of <I>ICMT</I> and <I>BRAF</I> resulted in a significant reduction of proliferation in these cells. However, the reduction did not exceed independent inactivation of <I>ICMT</I> or <I>BRAF</I>. These results indicate that targeting ICMT in human malignant melanoma could be an attractive strategy, which will be further explored.
PB Institutionen för kemi- och bioteknik, Chalmers tekniska högskola,
LA eng
LK http://publications.lib.chalmers.se/records/fulltext/141685.pdf
OL 30
