Prohibitin, relocated to the front ends, can control the migration directionality of colorectal cancer cells

Abstract

Directional migration is a cost-effective movement allowing invasion and metastatic spread of cancer cells. Although migration related to cytoskeletal assembly and microenvironmental chemotaxis has been elucidated, little is known about interaction between extracellular and intracellular molecules for controlling the migrational directionality. A polarized expression of prohibitin (PHB) in the front ends of CRC cells favors metastasis and is correlated with poor prognosis for 545 CRC patients. A high level of vascular endothelial growth factor (VEGF) in the interstitial tissue of CRC patients is associated with metastasis. VEGF bound to its receptor, neuropilin-1, can stimulate the activation of cell division cycle 42, which recruits intra-mitochondrial PHB to the front end of a CRC cell. This intracellular relocation of PHB results in the polymerization and reorganization of filament actin extending to the front end of the cell. As a result, the migration directionality of CRC cells is targeted towards VEGF. Together, these findings identify PHB as a key modulator of directional migration of CRC cells and a target for metastasis.

Cdc42 subcellular relocation in response to VEGF/NRP1 engagement is associated with the poor prognosis of colorectal cancer

“…The nude mouse model further revealed that CRC pulmonary metastases were associated with VEGF stimulation, NRP1 transfer, and Cdc42 activation, which corroborated the findings of our previous study and indicated that the directionality of protrusion formation and the high VEGF levels in interstitial tissues were consistent with metastatic production 3 . Cdc42 activation and relocation are at the core of the cell front assembly, which involves filopodia and invadopodia.…”

“…Both VEGF and activated Cdc42 stimulate LIM domain kinase 2 (LIMK2) to phosphorylate and activate cofilin, which, in turn, regulates actin dynamics 16,17 . Because it has been demonstrated that VEGF controls the directionality of migrating CRC cells 3 , we propose that VEGF/ NRP1 participates in the assembly of the cell front, such as the formation of filopodia and invadopodia and that Cdc42 might be involved in migration and invasion in response to VEGF stimulation, possibly uncovering a unique portrait of the molecular-subcellular frame.…”

“…Vascular endothelial growth factor (VEGF), including its variant VEGF165, in the microenvironment acts through an isoform-specific receptor, neuropilin-1 (NRP1), to attract the movement of cancer cells and is similar to neutrophil chemoattractant movements [2][3][4][5] . Our previous study showed that extracellular VEGF, not the intracellular VEGF of cancer cells, promoted the directional migration of colorectal cancer (CRC) cells, which improved the effectiveness of cell motility 3 . However, little is known regarding the subcellular transformation of VEGF/NRP1 engagement and its regulation of migrating cancer cells.…”

Prohibitin is a prognostic marker and therapeutic target to block chemotherapy resistance in Wilms’ tumor

“…In primary tumor tissue samples, however, PHB was significantly but modestly overexpressed in patients with relapsed Wilms' tumor as compared with those who had cured Wilms' tumor and normal kidney tissue (Figure 3 and Supplemental Figure 5). Thus, urine PHB elevation may be due to increased Wilms' tumor cell invasion and PHB release into renal tubules, as suggested by the increased invasiveness of colorectal and lung carcinomas with PHB overexpression (46)(47)(48). This possibility is further supported by the relatively higher frequency of abdominal Wilms' tumor relapse in patients with elevated urine PHB (Figure 2E).…”

Prohibitin promotes dedifferentiation and is a potential therapeutic target in neuroblastoma

“…Moreover, cancer cells expressing high levels of PHB show an enhanced capacity for migration and invasion, cellular qualities associated with metastatic disease (12,13). Notably, it was recently reported that PHB is required for dictating the directionality of invasive colorectal cancer cells (14). Although PHB has been extensively characterized in adult tumors, its role in pediatric cancers remains undefined.…”