Generic placeholder image

Current Cancer Drug Targets


ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Research Article

Combinatorial Inhibition of mTORC2 and Hsp90 Leads to a Distinctly Effective Therapeutic Strategy in Malignant Pheochromocytoma

Author(s): Xiaohua Zhang, Fengbin Gao and Shan Zhong*

Volume 19, Issue 9, 2019

Page: [698 - 706] Pages: 9

DOI: 10.2174/1568009619666190206120615


Background: Malignant pheochromocytoma (mPCC) is an uncommon tumor with poor prognosis, and no effective therapeutic strategy exists as yet. Discovering new and effective therapeutic strategies to improve prognosis is an urgent need.

Objective: To investigate whether a combinatorial inhibition of both mTORC2 and Hsp90 in PC12 cells could lead to a distinct anti-tumor effect in vitro and in vivo that was greater than the inhibition of mTORC2 or Hsp90 alone.

Methods: Targeting mTORC2 was assessed by knockdown of Rictor using shRNA, and 17-AAG was used to inhibit Hsp90 function.

Results: Combinatorial inhibition of both mTORC2 and Hsp90 could lead to a distinct anti-tumor effect in vitro that was greater than the inhibition of mTORC2 or Hsp90 alone. Inhibiting Hsp90 specifically could inhibit tumor growth of sh-Rictor cells in vivo, suggesting that the combinatorial inhibition of both mTORC2 and Hsp90 could lead to a distinct anti-tumor effect in vivo. Western blotting has shown that both p-Akt Ser473 and p-Akt Thr450 showed significantly decreased expression after targeting mTORC2, while p-Akt Thr308 did not. However, all three different p-AKTs, including p-Akt Ser473, p-Akt Thr450 and p-Akt Thr308, showed a significantly decreased expression in combinatorial inhibition of both mTORC2 and Hsp90. Collectively, it revealed that combinatorial inhibition of mTORC2 and Hsp90 could destabilize the Akt signaling.

Conclusion: Our results demonstrated that combinatorial inhibition of mTORC2 and Hsp90 could increase their anti-tumor effect and destabilize the Akt signaling in PC12 cells, suggesting a combinatorial inhibition of both mTORC2 and Hsp90 which might be an effective therapeutic strategy for mPCC.

Keywords: Malignant pheochromocytoma, mTORC2, Hsp90, antitumor, prognosis, Akt signaling.

Graphical Abstract
Eisenhofer, G.; Lenders, J.W.; Siegert, G.; Bornstein, S.R.; Friberg, P.; Milosevic, D.; Mannelli, M.; Linehan, W.M.; Adams, K.; Timmers, H.J.; Pacak, K. Plasma methoxytyramine: A novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status. Eur. J. Cancer, 2012, 48(11), 1739-1749.
Lenders, J.W.M.; Eisenhofer, G. Update on modern management of pheochromocytoma and paraganglioma. Endocrinol. Metab. (Seoul), 2017, 32(2), 152-161.
Druce, M.R.; Kaltsas, G.A.; Fraenkel, M.; Gross, D.J.; Grossman, A.B. Novel and evolving therapies in the treatment of malignant phaeochromocytoma: Experience with the mTOR inhibitor everolimus (RAD001). Horm. Metab. Res., 2009, 41(9), 697-702.
Jimenez, C.; Rohren, E.; Habra, M.A.; Rich, T.; Jimenez, P.; Ayala-Ramirez, M.; Baudin, E. Current and future treatments for malignant pheochromocytoma and sympathetic paraganglioma. Curr. Oncol. Rep., 2013, 15(4), 356-371.
Parenti, G.; Zampetti, B.; Rapizzi, E.; Ercolino, T.; Giache, V.; Mannelli, M. Updated and new perspectives on diagnosis, prognosis, and therapy of malignant pheochromocytoma/paraganglioma. J. Oncol., 2012. 872713
Zoncu, R.; Efeyan, A.; Sabatini, D.M. mTOR: From growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol., 2011, 12(1), 21-35.
Kawasaki, G.; Naruse, T.; Furukawa, K.; Umeda, M. mTORC1 and mTORC2 expression levels in oral squamous cell carcinoma: An immunohistochemical and clinicopathological study. Anticancer Res., 2018, 38(3), 1623-1628.
Martelli, A.M.; Buontempo, F.; McCubrey, J.A. Drug discovery targeting the mTOR pathway. Clin. Sci. (Lond.), 2018, 132(5), 543-568.
Jebali, A.; Dumaz, N. The role of RICTOR downstream of receptor tyrosine kinase in cancers. Mol. Cancer, 2018, 17(1), 39.
Giubellino, A.; Bullova, P.; Nölting, S.; Turkova, H.; Powers, J.F.; Liu, Q.; Guichard, S.; Tischler, A.S.; Grossman, A.B.; Pacak, K. Combined inhibition of mTORC1 and mTORC2 signaling pathways is a promising therapeutic option in inhibiting pheochromocytoma tumor growth: in vitro and in vivo studies in female athymic nude mice. Endocrinology, 2013, 154(2), 646-655.
Facchinetti, V.; Ouyang, W.; Wei, H.; Soto, N.; Lazorchak, A.; Gould, C.; Lowry, C.; Newton, A.C.; Mao, Y.; Miao, R.Q.; Sessa, W.C. The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C. EMBO J., 2008, 23, 27(14), 1932-1943.
Zhang, X.; Wang, X.; Xu, T.; Zhong, S.; Shen, Z. Targeting of mTORC2 may have advantages over selective targeting of mTORC1 in the treatment of malignant pheochromocytoma. Tumour Biol., 2015, 36(7), 5273-5281.
Zhang, F.; Lazorchak, A.S.; Liu, D.; Chen, F.; Su, B. Inhibition of the mTORC2 and chaperone pathways to treat leukemia. Blood, 21, 119(25), 6080-6088.
Zhang, J.Y.; Tao, L.Y.; Liang, Y.J.; Chen, L.M.; Mi, Y.J.; Zheng, L.S.; Wang, F.; She, Z.G.; Lin, Y.C.; To, K.K.W.; Fu, L.W. Anthracenedione derivatives as anticancer agents isolated from secondary metabolites of the mangrove endophytic fungi. Mar. Drugs, 2010, 8, 1469-1481.
Zhang, X.; Wang, X.; Qin, L.; Xu, T.; Zhu, Z.; Zhong, S.; Zhang, M.; Shen, Z. The dual mTORC1 and mTORC2 inhibitor PP242 shows strong antitumor activity in a pheochromocytoma PC12 cell tumor model. Urology, 2015, 85(1), 273. e1-7
Sato, S.; Fujita, N.; Tsuruo, T. Modulation of Akt kinase activity by binding to Hsp90. Proc. Natl. Acad. Sci. USA, 2000, 97(20), 10832-10837.
Xu, Y.; Zhu, Q.; Chen, D.; Shen, Z.; Wang, W.; Ning, G.; Zhu, Y. The HSP90 inhibitor 17-AAG exhibits potent antitumor activity for pheochromocytoma in a xenograft model. Tumour Biol., 2015, 36(7), 5103-5108.
Banerji, U. Heat shock protein 90 as a drug target: Some like it hot. Clin. Cancer Res., 2009, 15(1), 9-14.
Xu, Y.; Qi, Y.; Rui, W.; Zhu, Y.; Zhang, C.; Zhao, J.; Wei, Q.; Wu, Y.; Shen, Z.; Ning, G. Expression and diagnostic relevance of heat shock protein 90 and signal transducer and activator of transcription 3 in malignant pheochromocytoma. J. Clin. Pathol., 2013, 66(4), 286-290.
Lian, J.; Lin, D.; Xie, X.; Xu, Y.; Xu, L.; Meng, L.; Zhu, Y. NVP-AUY922, a novel HSP90 inhibitor, inhibits the progression of malignant pheochromocytoma in vitro and in vivo. OncoTargets Ther., 2017, 10, 2219-2226.
Giubellino, A.; Sourbier, C.; Lee, M.J.; Scroggins, B.; Bullova, P.; Landau, M.; Ying, W.; Neckers, L.; Trepel, J.B.; Pacak, K. Targeting heat shock protein 90 for the treatment of malignant pheochromocytoma. PLoS One, 2013, 8(2)e56083

© 2024 Bentham Science Publishers | Privacy Policy