Synthetic and Natural Inhibitors of Mortalin for Cancer Therapy

Abstract

Upregulation of stress chaperone Mortalin has been closely linked to the malignant transformation of cells, tumorigenesis, the progression of tumors to highly aggressive stages, metastasis, drug resistance, and relapse. Various in vitro and in vivo assays have provided evidence of the critical role of Mortalin upregulation in promoting cancer cell characteristics, including proliferation, migration, invasion, and the inhibition of apoptosis, a consistent feature of most cancers. Given its critical role in several steps in oncogenesis and multi-modes of action, Mortalin presents a promising target for cancer therapy. Consequently, Mortalin inhibitors are emerging as potential anti-cancer drugs. In this review, we discuss various inhibitors of Mortalin (peptides, small RNAs, natural and synthetic compounds, and antibodies), elucidating their anti-cancer potentials.

Keywords: Hsp70; cancer; chaperone; mortalin; natural and synthetic inhibitors.

Figure 1

Schematic representation of Mortalin structure and homology. The domain organization (constructed using I-TASSER [12]) and sequence-based homology with other closely related members of the Hsp70 family of proteins are shown.

Figure 2

Role of Mortalin in tumorigenesis. (A) Mortalin blocks the extrinsic and intrinsic apoptotic pathways in multiple ways, including inhibition of anti-apoptotic activities of p53, BclXL, Bcl2, Hsp60, Apaf1, AIF-1, and promoting apoptotic functions of Bax and PUMA [58]. (B) Increase cell proliferation by upregulating B-Raf-MEK1/2-ERK1/2, telomerase, IL1α, and HIF-1α signaling [59]. (C) Promotion of cell migration by activating hnRNP-K, PI-3K/Akt, p38-MAPK, NF-kB, MMP2, and MM9 [60]. (D) Stimulation of invasion and angiogenesis by activating Wnt/β-catenin, RECK-STAT3-MMP, and TGFβ-JNK-VEGF signaling involved in tumor metastasis [61,62].

Figure 3

Synthetic small molecule inhibitors of Mortalin.

Figure 4

Mortaparib(s) mediate the anti-cancer response through various mechanisms: (A) abrogation of Mortalin–p53 interaction, resulting in nuclear translocation and reactivation of p53 function; (B) inhibition of Mortalin–PARP1 interaction and DNA repair; (C) downregulation of telomerase function and inhibition of cell proliferation; (D) downregulation of Mortalin and compromised hnRNP-K function and cell migration; (E) downregulation of Mortalin and compromised mitochondrial integrity and increase in oxidative stress.

Figure 5

Compounds from natural sources as inhibitors of Mortalin.

Figure 6

Compounds from natural sources as inhibitors of Mortalin.