Drp1 regulates mitochondrial morphology and cell proliferation in cutaneous squamous cell carcinoma. Issue 3 (December 2017)

• Record Type: Journal Article
• Authors: Kitamura, Shinya; Yanagi, Teruki; Imafuku, Keisuke; Hata, Hiroo; Abe, Riichiro; Shimizu, Hiroshi
• Is Part Of: Journal of dermatological science. Volume 88:Issue 3(2017:Dec.)
• Page Start: 298
• Page End: 307
• Publication Date: 2017-12
• Subjects: Drp1 dynamin-related protein 1 -- SCC squamous cell carcinoma -- EGFR epidermal growth factor receptor -- HPEKp human primary epidermal keratinocyte progenitor -- NHDF normal human dermal fibroblasts -- FACS fluorescence-activated cell sorting -- MAPK mitogen-activated protein kinase -- TUNEL TdT-mediated dUTP nick end labeling; Drp1 -- Squamous cell carcinoma -- Cell cycle -- Proliferation -- MAPK; Dermatology -- Periodicals; Skin Diseases -- Periodicals; Dermatologie -- Périodiques; 616.5005
• DOI: 10.1016/j.jdermsci.2017.08.004
• Languages: English
• ISSNs: 0923-1811

Abstract

Highlights: Drp1 knockdown inhibits the proliferation of cutaneous SCC cells and leads to G2 cell cycle arrest. Loss of Drp1 elongated the mitochondrial network. Mitogen-activated protein kinase (MAPK) signaling activates the Drp1 pathway in cutaneous SCC. Gene knockdown of Drp1 inhibits tumor formation in vivo . Drp1 is overexpressed in cutaneous SCCs and correlates with the clinical stage. Abstract: Background: 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). Objective: To investigate the role of Drp1 in the tumorigenesis of cutaneous SCCs. Methods and results: 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 1/2 and Drp1 Ser616 . Also, PD325901 caused the dysregulation of the mitochondrial network. In tumor xenografts of DJM1 cells, the knockdown of Drp1 suppressed tumor growth in vivo, and clinically, the expression levels of Drp1 were higher in cutaneous SCCs than in normal epidermis, and correlated positively with the advanced clinical stages. Conclusion: 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.