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Review
. 2018 Mar 29;23(4):787.
doi: 10.3390/molecules23040787.

Regulating Cdc42 and Its Signaling Pathways in Cancer: Small Molecules and MicroRNA as New Treatment Candidates

Xing-Hua Xiao  1   2 , Lin-Chen Lv  3   4 , Jing Duan  5   6 , Ye-Meng Wu  7   8 , Shu-Jin He  9   10 , Zhen-Zhen Hu  11   12 , Li-Xia Xiong  13   14
Affiliations
Review

Regulating Cdc42 and Its Signaling Pathways in Cancer: Small Molecules and MicroRNA as New Treatment Candidates

Xing-Hua Xiao et al. Molecules. .

Abstract

Despite great improvements in the diagnosis and treatment of neoplasms, metastatic disease is still the leading cause of death in cancer patients, with mortality rates still rising. Given this background, new ways to treat cancer will be important for development of improved cancer control strategies. Cdc42 is a member of the Rho GTPase family and plays an important role in cell-to-cell adhesion, formation of cytoskeletal structures, and cell cycle regulation. It thus influences cellular proliferation, transformation, and homeostasis, as well as the cellular migration and invasion processes underlying tumor formation. Cdc42 acts as a collection point for signal transduction and regulates multiple signaling pathways. Moreover, recent studies show that in most human cancers Cdc42 is abnormally expressed and promoting neoplastic growth and metastasis. Regarding possible new treatments for cancer, miRNA and small molecules targeting Cdc42 and related pathways have been recently found to be effective on cancer. In this review, we analyze the newly recognized regulation mechanisms for Cdc42 and Cdc42-related signal pathways, and particularly new treatments using small molecules and miRNAs to inhibit the abnormal overexpression of Cdc42 that may slow down the metastasis process, improve cancer therapy and lead to novel strategies for development of antineoplastic drugs.

Keywords: Cdc42; Cdc42-related signaling pathways; cancer therapy; miRNAs; small molecules.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Regulation of Cdc42. Cdc42 switches between an inactive GDP-bound state and an active GTP-bound state. The GTP binding and hydrolysis cycle is highly regulated by intracellular molecules GEFs, GAPs, and GDIs. When Cdc42 is activated by various stimuli, Cdc42 can transiently interact with its downstream effector proteins, triggering cytoskeleton reorganization, alterations in the cell cycle, and transcription.
Figure 2
Figure 2
Three-dimensional structures of DH–PH domains. A ribbon diagram shown the DH domain (left dotted area) and PH domain (right dotted area) binding to Cdc42 (upper area). PDB accession number 1KZ7 [15]. GDP-bound Cdc42 (Rho GTPase) favor interactions with GEFs (as indicated by DH and PH in the figure). DH domain is essential for the biological activity of GEFs while PH domain can directly regulate the activity of the DH domain.
Figure 3
Figure 3
Downstream effector/adaptor proteins of Cdc42. Cdc42 can activate downstream proteins of Cdc42 including PAKs, ACK1, MLK3, IQGAPs, N-WASP, and PI3Ks. Ack1 promotes tumorigenesis by phosphorylating Wwox, Akt, and androgen receptors. PAK1, PAK2, and PAK3 can promote tumor progression and metastasis. MLK3 can phosphorylate and activate specific MAP2Ks, which activate specific MAPKs in sequence. The three major MAPKs are JNK/SAPK, ERK, and P38 MAPK. They can promote cancer cell migration and invasion. IQGAP1 promotes tumorigenesis and metastasis, while IQGAP2 may have the opposite effect. The function of IQGAP3 is not very clear at present. N-WASP can promote cancer cell migration and invasion by phosphorylating P38 MAPK. PIP2 is phosphorylated to PIP3 by PI3K, which leads to the phosphorylation of Akt. And Akt can phosphorylate and activate mTOR, which can promote tumor metastasis. Otherwise, PIP3 is quickly dephosphorylated to PIP2 under the action of PTEN.
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