Here, the expression of shPHB2-0 which only resulted in a medium knockdown of prohibitins caused a severe proliferation defect suggesting that the functions of prohibitins in proliferation and mitochondrial physiology differ. What did correlate was the occurrence of the adhesion defect and the observed reduction in proliferation. For instance, upon expression of shPHB2-0, cells already showed a decrease in cell-cell contact and cell-matrix formation and were sensitive to cell density. At the same time, the proliferation rate was strongly reduced in these cells. In prohibitin depleted cells, the ability to adhere to fibronectin is impaired. Experiments with Forskolin, an activator of cAMP/PKA signaling showed that prohibitin knockdown cells also have a defect in forming lamellipodia and focal adhesions, both being critical events for cell movement and migration. These findings are in accordance with our previous work showing siRNA-mediated silencing of PHB1 leads to a defect in cellular migration. Considering these results, the role of prohibitins in regulating cell proliferation seems to be associated with adhesion/migration signaling. Localization studies show prohibitins accumulate predominantly in mitochondria. However, both proteins belong to the SPFH domain family and are transmembrane proteins. Members of this family, e.g, Flotilin, are expressed in lipid rafts. Furthermore, we and others have previously isolated prohibitins from lipid rafts. It is therefore R428 conceivable that prohibitins play an important role at the plasma membrane, most likely as chaperones and scaffolding proteins as in mitochondria. Our findings clearly show that prohibitins are required for proliferation and growth of cancer cells and regulation of cellular homoeostasis. We could show their crucial role in cancer cell propagation and survival while implicating an important function in cell adhesion and cell contact formation. This leads to an overall perception of prohibitins as chaperoning proteins not only in the mitochondria but throughout the cell. The frequency of melanoma cases in Western countries has risen rapidly over the last years, and melanoma has become one of the most fatal cancers. Local melanoma can be cured by wide surgical excision at its early stage, but metastatic melanomas are usually incurable. Chemotherapy and cytokine adjuvant therapy are commonly used as a palliative systemic therapy in patients with advanced melanoma. However, the non-specificity and significant side effects of these therapies greatly limit their effective use in patients. Biochemotherapy, a combination therapy of cytokine adjuvant with chemotherapeutic agents, has been shown to improve response rates but not overall survival. Moreover, biochemotherapy has been found to be associated with increased toxicity. Recently, several Phase II/III clinical trials are ongoing for the use of CTLA4 monoclonal antibodies as a new promising strategy for the treatment of metastatic melanoma ; however, significant autoimmunerelated side effects have been increasingly observed.