pd-0325901 and Skin-Neoplasms

Dynamin-related protein 1 (Drp1) mediates mitochondrial fission. Recently, several studies have shown that Drp1 plays an important role in some cancers. However, little is known about Drp1 in cutaneous squamous cell carcinoma (SCC).. To investigate the role of Drp1 in the tumorigenesis of cutaneous SCCs.. We investigated cell proliferation, cell cycle, mitochondrial morphology, and MAPK signaling pathway using cutaneous SCC A431 and DJM1 cells that were transfected with shRNA vectors targeting Drp1. The Drp1 gene-knockdown SCC cells showed lower cell proliferation than scramble-control cells, as assessed by direct cell counting and clonogenic assays. DNA content analysis showed Drp1 knockdown to cause G2/M arrest. Morphologically, the depletion of Drp1 resulted in an elongated, hyper-fused mitochondrial network. The MEK inhibitor PD325901 suppressed cell proliferation, as well as inhibiting the phosphorylation of ERK. Our results reveal a crucial function for Drp1 in regulating tumor growth, mitochondrial morphology, and cell cycle in cutaneous SCC, suggesting that Drp1 could be a novel target for skin tumor therapies.

Topics: Aged; Aged, 80 and over; Animals; Benzamides; Carcinogenesis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Diphenylamine; Dynamins; Female; G2 Phase Cell Cycle Checkpoints; Gene Knockdown Techniques; GTP Phosphohydrolases; Humans; Male; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Mice, Nude; Microtubule-Associated Proteins; Middle Aged; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins; Neoplasm Staging; Phosphorylation; Quinazolinones; RNA Interference; RNA, Small Interfering; Skin Neoplasms; Xenograft Model Antitumor Assays

Oncogene-targeted therapies based on mutated BRAF- and/or MEK-specific inhibitors have been developed for melanoma treatment. Although these drugs induce tumor regression in a high percentage of patients, clinical responses are frequently limited in time and tumors often recur. Recent studies suggested that the combination of BRAF/MEK inhibition with immunotherapy could represent a promising strategy for the cure of melanoma. NK cells are suitable effectors for tumor immunotherapy. Here we show that PLX4032 (a mutant BRAFV600 inhibitor) had no effect on the functional properties of NK cells cultured in the presence of IL-2 or IL-15. In contrast, PD0325901 (a MEK inhibitor) induced the down-regulation of the main activating NK receptors and inhibited NK cell function. Importantly, PD0325901 did not affect the anti-tumor activity of NK cells that had been exposed to a combination of IL-15 and IL-18. In addition, both PLX4032 and PD0325901 did not exert any inhibitory effect on in vitro IL-2 or IL-15 pre-activated NK cells.Our data may provide a rationale for future clinical protocols that combine IL-15/IL-18 cytokine administration with MEK inhibitors. In addition, they suggest that oncogene-targeting drugs are compatible with NK-based adoptive therapy.

Topics: Acrylonitrile; Aniline Compounds; Antineoplastic Agents; Apoptosis; Benzamides; Cell Line, Tumor; Cell Proliferation; Cell Survival; Diphenylamine; Down-Regulation; Flow Cytometry; Humans; Immunotherapy; Indoles; Interleukin-15; Interleukin-2; Killer Cells, Natural; Melanoma; Neoplasm Recurrence, Local; Oncogenes; Proto-Oncogene Proteins B-raf; Signal Transduction; Skin Neoplasms; Sulfonamides; Vemurafenib