Hsp90 inhibitor induces autophagy and apoptosis in osteosarcoma cells

Abstract

Heat shock protein 90 (Hsp90) is constitutively expressed at 2-10-fold higher levels in tumor cells compared to normal cells, suggesting that it may be critically important for tumor cell growth and survival. These features make Hsp90 a potential target for anticancer drug development. Inhibition of Hsp90 activity not only results in rapid degradation of Hsp90 client proteins but also induces apoptosis of various tumor cells. Hsp90 also plays an important role in autophagy. An Hsp90 inhibitor induces autophagy through inhibition of mTOR. It is still under debate whether chemotherapy-induced autophagy in tumor cells is a protective response or is invoked to promote cell death. The aim of this study was to examine the effects of the Hsp90 inhibitor, geldanamycin (GA), on KTHOS osteosarcoma cells. We further examined whether a combination of GA and the autophagy inhibitor 3-methyl-adenine (3-MA) enhanced GA-induced apoptosis in KTHOS cells. GA had an inhibitory effect on cell proliferation and inhibited the Akt/mTOR signaling pathway in KTHOS cells. GA alone induced autophagy and apoptosis in KTHOS cells, but treatment with a combination of GA and 3-MA suppressed autophagy and induced apoptosis to a much greater extent than GA alone in these cells. It was considered that the autophagy inhibitor 3-MA suppressed a protective mechanism induced by Hsp90 inhibitor in tumor cells and induced apoptosis. Therefore, the combination of an Hsp90 inhibitor and an autophagy inhibitor may be an effective treatment for osteosarcoma because this combination effectively induces apoptotic pathways.

Proteomic Profiling for Identification of Novel Biomarkers Differentially Expressed in Human Ovaries from Polycystic Ovary Syndrome Patients

“…These include genes involved in the insulin signaling pathway [23], proteins associated with cell proliferation [24], and estrogen and progesterone receptor subtypes [25]. In the present study, five proteins (lamin A, vimentin, tubulin-β chain, ANXA6, and SERPINC1) were reported previously, [22] and thirteen proteins were identified for the first time being differentially expressed in PCOS as compared to the normal ovaries.…”

“…HSP90B1 is demonstrated to be involved in the growth of cancerous cells, and HSP90B1 inhibitors can reverse cancer cell growth and increase survival [24–29]. HSP90B1 is an important chaperone protein that interacts with multiple intracellular receptors and transcription factors, has a role in stabilization of client proteins from protease degradation, such as AKT, I ĸB-α, glucocorticoid, and progesterone receptors [24, 25, 30], and responsible for client protein stability and maturation after activation [31]. However, the underlying molecular mechanisms of HSP90B1 on ovarian cell function remain unknown.…”

Deoxyelephantopin Induces Reactive Oxygen Species-Mediated Apoptosis and Autophagy in Human Osteosarcoma Cells

“…Autophagy plays a protective role when cells encounter environmental stresses, such as starvation or pathogen infection [34, 35]. This type of autophagy benefits cell survival, but excessive autophagy can result in autophagic cell death [36].…”

Hsp90 regulates autophagy and plays a role in cancer therapy

“…As expected, the combination of GA and the autophagy inhibitor 3-MA could significantly enhance GA-induced apoptosis and suppress autophagy [50]. Undoubtedly, these also demonstrate that Hsp90 can regulate autophagy.…”

“…Recently, it has been reported that GA induces autophagy by inhibiting the Akt/mTOR signaling pathway and induces a caspase-dependent apoptosis in osteosarcoma cells [50]. As expected, the combination of GA and the autophagy inhibitor 3-MA could significantly enhance GA-induced apoptosis and suppress autophagy [50].…”