Targeting prohibitin with small molecules to promote melanogenesis and apoptosis in melanoma cells

• DOI: 10.1016/j.ejmech.2018.06.052
• Publication Date: 2018-06-23T16:18:36Z
• Authors: Amel Djehal; Mohammad Krayem; Ahmad Najem; Hassan Hammoud; Thierry Cresteil; Canan G. Nebigil; Dong Wang; Peng Yu; Embarek Bentouhami; Ghanem E. Ghanem; Laurent Désaubry
• Keywords: Eumelanogenesis; Small Molecule Libraries -- chemistry -- pharmacology; Repressor Proteins -- chemistry -- pharmacology; [SDV.CAN]Life Sciences [q-bio]/Cancer; Antineoplastic Agents; Apoptosis; Drug Screening Assays; Cell Proliferation -- drug effects; Dose-Response Relationship; Small Molecule Libraries; Structure-Activity Relationship; 03 medical and health sciences; Prohibitins; LC3; Tumor Cells, Cultured; Humans; Melanoma; Antineoplastic Agents -- chemistry -- pharmacology; Cancer; Cell Proliferation; MITF; 0303 health sciences; Cultured; Dose-Response Relationship, Drug; Molecular Structure; Melanocytes -- drug effects; Antitumor; Sciences bio-médicales et agricoles; [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences; Melanoma -- drug therapy -- pathology; Tumor Cells; 3. Good health; Repressor Proteins; ERK; Triazine; Melanocytes; Drug; Drug Screening Assays, Antitumor; Apoptosis -- drug effects

Prohibitins 1 and 2 (PHB1/2) are scaffold proteins that are involved in both melanogenesis and oncogenic pathways. We hypothesized that a PHB1 ligand, melanogenin, may display anti-cancer effects in addition to its known melanogenic activity in melanocytes. Here, we disclose a convenient synthesis of melanogenin, and its analogs. We found that, among 57 new melanogenin analogs, two (Mel9 and Mel41) significantly promoted both melanogenesis in melanocytes by activating one of the PHB2-interacting proteins, microtubule-associated protein light chain 3 (LC3), and upregulating the expression of microphthalmia associated transcription factor (MITF). These analogs also activate ERK. Besides, in addition to their promelanogenic activities, we uncovered that melanogenin and its active analogs induce apoptosis in several cancer cell lines, including melanoma cells, and that this effect is caused by an inhibition of AKT survival pathway. Our findings present a new putative function for PHBs as regulators of LC3/ERK/MITF melanogenic signaling, and suggest that Mel9 and Mel41 may provide the basis for the development of new drugs candidates to treat melanoma and other types of cancers.