Targeting ROCK/LIMK/cofilin signaling pathway in cancer
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Online ISSN 1976-3786 Print ISSN 0253-6269
REVIEW
Targeting ROCK/LIMK/cofilin signaling pathway in cancer Mee-Hyun Lee1,2 • Joydeb Kumar Kundu3 • Jung-Il Chae4 • Jung-Hyun Shim2,5
Received: 31 January 2019 / Accepted: 2 April 2019 Ó The Pharmaceutical Society of Korea 2019
Abstract Rho-associated coiled-coil-containing protein kinase (ROCK)/Lin11, Isl-1 and Mec-3 kinase (LIMK)/cofilin-signaling cascades are stimulated by receptor tyrosine kinases, G protein-coupled receptors, integrins and its ligands, growth factors, hormones, fibronectin, collagen, and laminin. Activated signaling cascades can cause transit from normal cells to cancer cells by modulating actin/filament dynamics. In various cancers including breast, prostate, and colorectal cancers, high expression or activity of each cascade protein is significantly associated with poor survival rate of patients as well as aggressive metastasis. Silencing ROCK, LIMK, or cofilin can abrogate their activities and inhibit cancer cell growth, invasion, and metastasis. Therefore ROCK/LIMK/cofilin signaling proteins might be good candidates to develop cancer prevention strategies or therapeutics. Currently, netarsudil, a ROCK inhibitor, is only used in clinical patients for glaucoma or ocular hypertension, but not for cancer. In this review, we will discuss comprehensive ROCK/ & Jung-Hyun Shim [email protected] 1
Basic Medical College, Zhengzhou University, Zhengzhou 450001, Henan, China
2
China-US (Henan) Hormel Cancer Institute, No.127, Dongming Road, Jinshui District, Zhengzhou 450008, Henan, China
3
Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton, AB T6G 2R3, Canada
4
Department of Dental Pharmacology, School of Dentistry, BK21 Plus, Chonbuk National University, Chonju 54896, Republic of Korea
5
Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan, Jeonnam 58554, Republic of Korea
LIMK/cofilin signaling pathway in cancers and its inhibitors for developing cancer therapy. Keywords ROCK LIMK Cofilin Signaling pathways Inhibitors Cancer therapy
Introduction Rho-associated coiled-coil-containing protein kinase (ROCK)/Lin11, Isl-1 and Mec-3 kinase (LIMK)/cofilin signaling pathway plays important roles in carcinogenic processes such as proliferation, survival, migration, and invasion of tumor cells (Manetti 2012; Chang et al. 2015; Tang et al. 2018) (Fig. 1). Growth factors including transforming growth factor (TGF)-b can activate guaninenucleotide exchange factors (GEFs) and Rho GTPases by binding to receptor tyrosine kinases and relay signals to down-stream targets LIMKs and cofilins by phosphorylation, thereby inducing actin cytoskeleton reorganization, actin dynamics of nuclear or cytoplasm, and gene transcription (Philimonenko et al. 2004; Kapoor and Shen 2014; Chang et al. 2015). Therefore, the ROCK-LIMK/cofilin signaling cascade can cause promote proliferation and motility of cancer cells as a result of actin remodeling. ROCK is a serine/threonine kinase of protein kinase (PK)A, G, C (PKA, PK
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