c-Abl and Arg induce cathepsin-mediated lysosomal degradation of the NM23-H1 metastasis suppressor in invasive cancer

Abstract

Metastasis suppressors comprise a growing class of genes whose downregulation triggers metastatic progression. In contrast to tumor suppressors, metastasis suppressors are rarely mutated or deleted, and little is known regarding the mechanisms by which their expression is downregulated. Here, we demonstrate that the metastasis suppressor, NM23-H1, is degraded by lysosomal cysteine cathepsins (L,B), which directly cleave NM23-H1. In addition, activation of c-Abl and Arg oncoproteins induces NM23-H1 degradation in invasive cancer cells by increasing cysteine cathepsin transcription and activation. Moreover, c-Abl activates cathepsins by promoting endosome maturation, which facilitates trafficking of NM23-H1 to the lysosome where it is degraded. Importantly, the invasion- and metastasis-promoting activity of c-Abl/Arg is dependent on their ability to induce NM23-H1 degradation, and the pathway is clinically relevant as c-Abl/Arg activity and NM23-H1 expression are inversely correlated in primary breast cancers and melanomas. Thus, we demonstrate a novel mechanism by which cathepsin expression is upregulated in cancer cells (via Abl kinases). We also identify a novel role for intracellular cathepsins in invasion and metastasis (degradation of a metastasis suppressor). Finally, we identify novel crosstalk between oncogenic and metastasis suppressor pathways, thereby providing mechanistic insight into the process of NM23-H1 loss, which may pave the way for new strategies to restore NM23-H1 expression and block metastatic progression.

Multifunctional Abl kinases in health and disease

“…Abl kinases also promote endosome maturation and trafficking of proteins to the lysosome for degradation (Fiore et al, 2014;Yogalingam and Pendergast, 2008). Trafficking of early endosomes and lysosomes along microtubules facilitates organelle motility and fusion events.…”

“…Moreover, Abl kinases have been shown to promote invasion and metastasis of melanoma cells (Fiore et al, 2014). ABL2 localizes to invadopodia and was shown to regulate the maturation of invadopodia by linking activation of the EGFR and Src kinases to tyrosine phosphorylation of cortactin (Mader et al, 2011).…”

The Emerging Role of ABL Kinases in Solid Tumors

“…Enhanced activation of the ABL kinases downstream of multiple receptor tyrosine kinases (RTKs) including the platelet-derived growth factor receptor (PDGFR), the ERBB family member EGF receptor (EGFR), and the hepatocyte growth factor receptor (MET) has been reported by multiple groups [4, 41, 42]. Cancer cells expressing activated ERBB receptors exhibited rapid EGF-induced ABL kinase stimulation [43].…”

“…Knockdown of ABL2 alone decreased cancer cell invasion and intravasation following implantation of MDA-MB-231 cells in the mammary fat pad [53]. A requirement for ABL kinases for invasion and metastasis of melanoma cells was also shown, which may be mediated in part by the NM23-H1 metastasis suppressor [42]. Active ABL kinases induced cathepsin-dependent lysosomal degradation of NM23-H1 in melanoma and breast cancer cells.…”

The NDPK/NME superfamily: state of the art

“…94 Second, SWI/SNF chromatin remodelers-associated PRMT5 (protein arginine methyltransferase 5) is directly involved in transcriptional repression of NME1. 95 Third, NME1 could be regulated at the protein level by (i) lysosomal cysteine cathepsins, proteases with known roles in invasion and metastasis, which directly cleave and degrade NME1, 96 and (ii) the E3 ubiquitin ligase SCF-FBXO4, which interacts with NME1 to mediate its polyubiquitination and subsequent proteosomal degradation. 97 Finally, a field worth investigation in regard to NME1 tumoral expression is the potential role of the tumoral stroma, in particular, cancer-associated fibroblasts (CAF), which have been shown to promote cancer invasion and migration, and metastasis in many different models.…”