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Hsp90 inhibitor induces autophagy and apoptosis in osteosarcoma cells.

Mori M, Hitora T, Nakamura O, Yamagami Y, Horie R, Nishimura H, Yamamoto T - Int. J. Oncol. (2014)

Bottom Line: The aim of this study was to examine the effects of the Hsp90 inhibitor, geldanamycin (GA), on KTHOS osteosarcoma cells.GA had an inhibitory effect on cell proliferation and inhibited the Akt/mTOR signaling pathway in KTHOS cells.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopaedic Surgery, Kagawa University School of Medicine, Miki‑cho, Kagawa 761‑0793, Japan.

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‑methyladenine (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.

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Geldanamycin (GA) induces apoptosis in KTHOS cells. Western blot analysis of caspase and PARP cleavage in KTHOS cells treated with various concentrations of GA for 24 h. α-tubulin was used as a loading control.
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f5-ijo-46-01-0047: Geldanamycin (GA) induces apoptosis in KTHOS cells. Western blot analysis of caspase and PARP cleavage in KTHOS cells treated with various concentrations of GA for 24 h. α-tubulin was used as a loading control.

Mentions: We next examined the effect of GA on caspase activity to determine if GA induces caspase-dependent apoptosis in KTHOS cells. Western blot analysis indicated that treatment of KTHOS cells with concentrations of GA ranging from 0.01 to 10 μM for 24 h resulted in dose-dependent cleavage of PARP, as well as activation of caspase-8 and -9 (Fig. 5). These results suggest the ability of GA to induce apoptosis in a caspase-dependent manner in KTHOS cells.


Hsp90 inhibitor induces autophagy and apoptosis in osteosarcoma cells.

Mori M, Hitora T, Nakamura O, Yamagami Y, Horie R, Nishimura H, Yamamoto T - Int. J. Oncol. (2014)

Geldanamycin (GA) induces apoptosis in KTHOS cells. Western blot analysis of caspase and PARP cleavage in KTHOS cells treated with various concentrations of GA for 24 h. α-tubulin was used as a loading control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4238730&req=5

f5-ijo-46-01-0047: Geldanamycin (GA) induces apoptosis in KTHOS cells. Western blot analysis of caspase and PARP cleavage in KTHOS cells treated with various concentrations of GA for 24 h. α-tubulin was used as a loading control.
Mentions: We next examined the effect of GA on caspase activity to determine if GA induces caspase-dependent apoptosis in KTHOS cells. Western blot analysis indicated that treatment of KTHOS cells with concentrations of GA ranging from 0.01 to 10 μM for 24 h resulted in dose-dependent cleavage of PARP, as well as activation of caspase-8 and -9 (Fig. 5). These results suggest the ability of GA to induce apoptosis in a caspase-dependent manner in KTHOS cells.

Bottom Line: The aim of this study was to examine the effects of the Hsp90 inhibitor, geldanamycin (GA), on KTHOS osteosarcoma cells.GA had an inhibitory effect on cell proliferation and inhibited the Akt/mTOR signaling pathway in KTHOS cells.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopaedic Surgery, Kagawa University School of Medicine, Miki‑cho, Kagawa 761‑0793, Japan.

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‑methyladenine (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.

Show MeSH
Related in: MedlinePlus