Novel Insights into the Roles of Rho Kinase in Cancer

Abstract

Rho-associated coiled-coil kinase (ROCK) is a major downstream effector of the small GTPase RhoA. The ROCK family, consisting of ROCK1 and ROCK2, plays a central role in the organization of the actin cytoskeleton, and is involved in a wide range of fundamental cellular functions such as contraction, adhesion, migration, proliferation, and apoptosis. Since the discovery of effective inhibitors such as fasudil and Y27632, the biological roles of ROCK have been extensively explored in numerous diseases, including cancer. Accumulating evidence supports the concept that ROCK plays important roles in tumor development and progression through regulating many key cellular functions associated with malignancy, including tumorigenicity, tumor growth, metastasis, angiogenesis, tumor cell apoptosis/survival and chemoresistance as well. This review focuses on the new advances of the most recent five years from the studies on the roles of ROCK in cancer development and progression; the discussion is mainly focused on the potential value of ROCK inhibitors in cancer therapy.

ROCK inhibitor enhances the growth and migration of BRAF‐mutant skin melanoma cells

“…Rho‐associated protein kinase (ROCK), a serine‐threonine kinase belonging to the AGC (PKA/PKG/PKC) family, regulates cell shape and migration by acting on the cytoskeleton; it also plays an important role in modulating cell survival, proliferation and apoptosis through multiple downstream targets . The 2 known mammalian ROCK isoforms, ROCK1 and ROCK2, are 62% homologous overall and 92% homologous in their kinase domain . Because ROCK affects multiple biological processes, ROCK inhibitors have been tested for clinical effects, including on cancer .…”

“…Because ROCK affects multiple biological processes, ROCK inhibitors have been tested for clinical effects, including on cancer . The ROCK inhibitor Fasudil was approved for clinical treatment of cerebral vasospasm in Japan and China . Y‐27632, another well‐established ROCK inhibitor, has been widely used to study the biological and pharmacological functions of ROCK in vitro and in vivo .…”

“…The ROCK inhibitor Fasudil was approved for clinical treatment of cerebral vasospasm in Japan and China . Y‐27632, another well‐established ROCK inhibitor, has been widely used to study the biological and pharmacological functions of ROCK in vitro and in vivo . A majority of studies have shown that ROCK functions as a positive regulator in tumor cell growth, migration, metastasis and survival .…”

“…Y‐27632, another well‐established ROCK inhibitor, has been widely used to study the biological and pharmacological functions of ROCK in vitro and in vivo . A majority of studies have shown that ROCK functions as a positive regulator in tumor cell growth, migration, metastasis and survival . For instance, Y‐27632 decreased breast cancer cell invasion/migration in vitro and metastasis in vivo; Y‐27632 was reported to reduce invasive potential of ovarian cancer and colon cancer cells; Y‐27632‐was shown to suppress progression of hepatocellular carcinoma through negative regulation of its proliferation and migration .…”

Rho signaling research: history, current status and future directions

“… showed that ROCK activation in mouse pancreatic ductal adenocarcinoma cells increased their invasive growth into a three‐dimensional collagen matrix by extensive induction of matrix metalloproteinases and increased matrix remodeling. These findings combined together suggest that Rho‐ROCK signaling is not the primary cause but critical for several important phenotypes of cancer, which may be exploited therapeutically in combination with other anticancer therapies .…”