The therapeutic target Hsp90 and cancer hallmarks

Abstract

Hsp90 is a major molecular chaperone that is expressed abundantly and plays a pivotal role in assisting correct folding and functionality of its client proteins in cells. The Hsp90 client proteins include a wide variety of signal transducing molecules such as protein kinases and steroid hormone receptors. Cancer is a complex disease, but most types of human cancer share common hallmarks, including self-sufficiency in growth signals, insensitivity to growth-inhibitory mechanism, evasion of programmed cell death, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis. A surprisingly large number of Hsp90-client proteins play crucial roles in establishing cancer cell hallmarks. We start the review by describing the structure and function of Hsp90 since conformational changes during the ATPase cycle of Hsp90 are closely related to its function. Many co-chaperones, including Hop, p23, Cdc37, Aha1, and PP5, work together with Hsp90 by modulating the chaperone machinery. Post-translational modifications of Hsp90 and its cochaperones are vital for their function. Many tumor-related Hsp90-client proteins, including signaling kinases, steroid hormone receptors, p53, and telomerase, are described. Hsp90 and its co-chaperones are required for the function of these tumor-promoting client proteins; therefore, inhibition of Hsp90 by specific inhibitors such as geldanamycin and its derivatives attenuates the tumor progression. Hsp90 inhibitors can be potential and effective cancer chemotherapeutic drugs with a unique profile and have been examined in clinical trials. We describe possible mechanisms why Hsp90 inhibitors show selectivity to cancer cells even though Hsp90 is essential also for normal cells. Finally, we discuss the "Hsp90-addiction" of cancer cells, and suggest a role for Hsp90 in tumor evolution.

Fig. (1).. Schematic illustrations of Hsp90 structure.

(A) Domain architecture for human and yeast Hsp90. NTD, LK, MD, and CTD stand for N-terminal domain, linker or charged region, middle domain, and C-terminal domain. (B) Schematic representation of the two Hsp90 conformations, the open state, and the ATP-bound closed state. N, M, C, and A stand for N-terminal domain, middle domain, C-terminal domain, and ATP.

Fig. (2).. Hsp90 and the hallmarks of cancer cells.

Six acquired capabilities of cancer cells are illustrated. These hallmarks of cancer cells are established by malfunctions of many Hsp90-dependent signal transduction molecules. Inhibition of Hsp90 by specific inhibitors suppresses all the tumor-promoting signalling pathways concomitantly.

Fig. (3).. Hsp90-client proteins in proliferation stimulating signal transduction networks.

Hsp90 is required for the correct folding and function of many signalling protein kinases that is crucial for cell proliferation. Hsp90-client kinases are boxed with shaded (blue in the Web version) rectangles.

Fig. (4).. Hsp90-client kinases that play a role in cell cycle regulation, cell division machinery control, and cell cycle checkpoint.

Hsp90 is required for the correct folding and function of many signalling protein kinases that is crucial for cell cycle regulation. Hsp90-client kinases are boxed with shaded (blue in the Web version) rectangles.

Fig. (5).. Regulation of Hsp90 chaperone activity by CK2 dependent phosphorylation.

CK2 phosphorylates three sites in Hsp90 (human numbering) and reduces the chaperone function of Hsp90. CK2 itself is a client protein for active Hsp90.

Fig. (6).. Regulation of a co-chaperone Cdc37 by CK2-dependent phosphorylation and PP5-dependent dephosphorylation.

CK2 phosphorylates Ser13 (mammalian numbering) and the phosphorylation is essential for the protein kinase binding and chaperone activity of Cdc37. CK2 itself is a binding partner for active Cdc37, forming a positive feedback regulatory mechanism. Phospho-Cdc37 is dephosphorylated by an Hsp90 co-chaperone phosphatase PP5. Cdc37 (both phosphorylated and non-phosphorylated), CK2, and PP5 are all Hsp90-binding partners.

Fig. (7).. Hsp90-client proteins in the signal transduction system of cell apoptosis.

Hsp90 is required for the correct folding and function of many molecules involved in stress responses leading to apoptosis. Hsp90-cliet proteins are boxed with shaded (blue in the Web version) rectangles. Wild-type p53 is a weak Hsp90-client.

Fig. (8).. Hsp90-client proteins in the cell survival signal transduction systems.

Hsp90 is required for the correct folding and function of many protein kinases involved in cell survival signalling. Hsp90-client kinases are boxed with shaded (blue in the Web version) rectangles.

Fig. (9).. Various Hsp90-client proteins, their biochemical activities, and the role in tumor progression.

Several other important Hsp90-client proteins involved in the tumor progression processes are listed along with their biochemical activities and molecular functions.

Fig. (10).. Hsp90-addiction of cancer cells.

Schematic illustration showing the different quantitative requirement for Hsp90 between normal and cancer cells. Without Hsp90 inhibitor (A), the level of Hsp90 activity may be sufficient for both normal and cancer cells. When treated with Hsp90 inhibitors (B), the level of Hsp90 activity is reduced, and the remaining Hsp90 activity is sufficient for normal cells, but not for cancer cells, inducing the selective killing of cancer cells.