Supporting a Role for the GTPase Rab7 in Prostate Cancer Progression

Abstract

Invasion and subsequent metastasis is the major cause of death from most cancers including prostate cancer. Herein we report on the potential tumor suppressive properties of Rab7, a GTPase that regulates trafficking of lysosomes. The movement of lysosomes to the cell surface in response to environmental cues increases the secretion of proteinases and cell invasion. We determined that Troglitazone and other members of the Thiazolidinedione family inhibit cell-surface directed lysosome trafficking and cathepsin B secretion through a Rab7-dependent mechanism. Moreover, Rab7 shRNA expressing cells were found to be more invasive in vitro and in vivo. Increased invasiveness was accompanied by elevated expression of the c-Met receptor and prolonged downstream signaling, thereby supporting a role for Rab7 as a mediator of signaling down-regulation. Taken together, these results suggested that Rab7 acts as a negative regulator of prostate tumor growth and invasion, providing further evidence for its potential as a tumor suppressor.

Mechanisms and functions of lysosome positioning

“…In addition, Rab7 mRNA levels have been found to be downregulated in biopsies of prostate cancer epithelial cells, but not in the surrounding stromal cells or in tissue from benign prostatic hyperplasia (Steffan et al, 2014). This change in Rab7 levels is thought to be pathogenic because peripheral redistribution of lysosomes caused by Rab7 knockdown can be associated with increased cancer cell invasiveness (Steffan et al, 2014). In contrast, depletion of Arl8b prevents lysosome dispersal in response to hepatocyte growth factor, epidermal growth factor and acidic extracellular pH, and diminishes invasive growth of prostate cancer cells .…”

“…Moreover, expression of an active form of the ErbB2 oncogene in a breast cancer cell line increased the amounts of KIF5B and its association with lysosomes (Cardoso et al, 2009). In addition, Rab7 mRNA levels have been found to be downregulated in biopsies of prostate cancer epithelial cells, but not in the surrounding stromal cells or in tissue from benign prostatic hyperplasia (Steffan et al, 2014). This change in Rab7 levels is thought to be pathogenic because peripheral redistribution of lysosomes caused by Rab7 knockdown can be associated with increased cancer cell invasiveness (Steffan et al, 2014).…”

Evolving role of adiponectin in cancer-controversies and update

“…Rivoglitazone has been shown to have beneficial effects on the insulin resistance, type 2 diabetes and atherosclerosis in vivo partly through its substantial effects on APN 176,177 . However, its effects on cancer remain to be studied.…”

The role of endocytic Rab GTPases in regulation of growth factor signaling and the migration and invasion of tumor cells

“…[110][111][112] Lysosome trafficking is an important feature of the endocytic pathway particularly in the degradation growth-factor receptors and/or ligands and is regulated by Rab7. 113,114 Disruption of the endocytic pathway in EGF mediated signaling in cancer cells can be rescued by the activation of the autophagy and lysosomal pathway. Bif1, a tumor suppressor and Bax family member, led to the recruitment of Rab7 to the early endosome and facilitated the loss of cell migration of breast cancer cells by directing the degradation of the EGFR.…”

“…113 Rab7 has also been associated with MT1-MMP secretion and the promotion of cell migration and invasion as it was determined that the dominant-negative mutant of Rab7 impairs both processes. 114 On the other hand, early stage melanomas promoted tumor progression via Rab7 regulation of the lysosomal pathway, where high expression of Rab7 was an indicator of the high metastatic risk (increased proliferative and invasive outcome) in patients. 118 The contrary role of Rab7 may be attributed to cancer type, stage and specific growth-factor stimulus.…”