Isoprenylcysteine carboxyl methyltransferase (ICMT) promotes invadopodia formation and metastasis in cancer cells.

Isoprenyl cysteine carboxyl methyltransferase (ICMT) catalyzes the last step of the prenylation pathway. Previously, we found that high ICMT levels enhance tumorigenesis in vivo and that its expression is repressed by the p53 tumor suppressor. Based on evidence suggesting that some ICMT substrates affect invasive traits, we wondered if this enzyme may promote metastasis. In this work, we found that ICMT overexpression enhanced lung metastasis in vivo. Accordingly, ICMT overexpression also promoted cellular functions associated with aggressive phenotypes such as migration and invasion in vitro. Considering that some ICMT substrates are involved in the regulation of actin cytoskeleton, we hypothesized that actin-rich structures, associated with invasion and metastasis, may be affected. Our findings revealed that ICMT enhanced the formation of invadopodia. Additionally, by analyzing cancer patient databases, we found that ICMT is overexpressed in several tumor types. Furthermore, the concurrent expression of ICMT and CTTN, which encodes a crucial component of invadopodia, showed a significant correlation with clinical outcome. In summary, our work identifies ICMT overexpression as a relevant alteration in human cancer that promotes the development of metastatic tumors.

The p53 tumor suppressor regulates AKR1B1 expression, a metastasis-promoting gene in breast cancer.

Alteration of metabolism in cancer cells is a central aspect of the mechanisms that sustain aggressive traits. Aldo-keto reductase 1 B1 (AKR1B1) catalyzes the reduction of several aldehydes to alcohols consuming NADPH. Nevertheless, the ability of AKR1B1 to reduce different substrates renders difficult to comprehensively ascertain its biological role. Recent evidence has implicated AKR1B1 in cancer; however, the mechanisms underlying its pro-oncogenic function remain largely unknown. In this work, we report that AKR1B1 expression is controlled by the p53 tumor suppressor. We found that breast cancer patients bearing wild-type TP53 have reduced AKR1B1 expression. In cancer cell lines, p53 reduced AKR1B1 mRNA and protein levels and repressed promoter activity in luciferase assays. Furthermore, chromatin immunoprecipitation assays indicated that p53 is recruited to the AKR1B1 promoter. We also observed that AKR1B1 overexpression promoted metastasis in the 4T1 orthotopic model of triple-negative breast cancer. Proteomic analysis of 4T1 cells overexpressing AKR1B1 showed that AKR1B1 exerts a marked effect on proteins related to metabolism, with a particular impact on mitochondrial function. This work provides novel insights on the link between the p53 pathway and metabolism in cancer cells and contributes to characterizing the alterations associated to the pathologic role of AKR1B1.

Beyond the Mevalonate Pathway: Control of Post-Prenylation Processing by Mutant p53.

Missense mutations in the TP53 gene are among the most frequent alterations in human cancer. Consequently, many tumors show high expression of p53 point mutants, which may acquire novel activities that contribute to develop aggressive tumors. An unexpected aspect of mutant p53 function was uncovered by showing that some mutants can increase the malignant phenotype of tumor cells through alteration of the mevalonate pathway. Among metabolites generated through this pathway, isoprenoids are of particular interest, since they participate in a complex process of posttranslational modification known as prenylation. Recent evidence proposes that mutant p53 also enhances this process through transcriptional activation of ICMT, the gene encoding the methyl transferase responsible for the last step of protein prenylation. In this way, mutant p53 may act at different levels to promote prenylation of key proteins in tumorigenesis, including several members of the RAS and RHO families. Instead, wild type p53 acts in the opposite way, downregulating mevalonate pathway genes and ICMT. This oncogenic circuit also allows to establish potential connections with other metabolic pathways. The demand of acetyl-CoA for the mevalonate pathway may pose limitations in cell metabolism. Likewise, the dependence on S-adenosyl methionine for carboxymethylation, may expose cells to methionine stress. The involvement of protein prenylation in tumor progression offers a novel perspective to understand the antitumoral effects of mevalonate pathway inhibitors, such as statins, and to explore novel therapeutic strategies.