Glucocorticoid
receptor
activation
and chemotherapy
resistance
How cancer can evade apoptosis
Glucocorticoid receptor (GR) signaling is a newly identified
resistance mechanism
Recurrent malignancies like platinum-resistant ovarian cancer use cellular signaling pathways
to evade chemotherapy-induced apoptosis. Glucocorticoid receptor activation is a pathway
that can reframe our understanding of ovarian cancer chemotherapy resistance.1
Glucocorticoid Receptor Activation and Chemotherapy Resistance
Leading oncologists in ovarian cancer help to untangle the connections between chemotherapy resistance, glucocorticoid receptor activation, and apoptosis.
GR activation starts
with cortisol
The stress hormone
Cortisol, commonly known as the stress
hormone, is an endogenous glucocorticoid
that plays an important role in a range of
cellular and physiological functions.2
GR activation in cancer
By activating the glucocorticoid receptor, cortisol
can promote tumor progression by suppressing
pro-apoptotic pathways used by cytotoxic agents.3
High glucocorticoid receptor expression in ovarian
cancer correlates with shorter progression-free
survival, and preclinical studies have shown the impact that physiological cortisol levels can have on chemotherapy-mediated cell death.3-6
How GR activation can suppress apoptosis
Competing signals impact resistance
Research indicates that glucocorticoid receptor (GR) activation may reduce the activity of
chemotherapy in ovarian cancer cells. When activated, the GR promotes the expression of anti-
apoptotic genes which suppress the signaling pathways that taxanes utilize to induce microtubule
stabilization, mitotic arrest, and ultimately apoptosis.3
Molecular effects of DUSP1 and SGK1 expression
DUSP1 and SGK1 are 2 of the anti-apoptotic genes that can be expressed through GR
activation. They both act to prevent apoptosis through their own distinct molecular cascades.1
DUSP1
Increase in active anti-apoptotic proteins1
SGK1
Reduction in pro-apoptotic
proteins1,3,7,8,11-13
Evidence suggests GR activation has a key
role in treatment resistance3
Research is ongoing to further understand this key pathway integral to chemotherapy resistance seen in
platinum-resistant ovarian cancer and other solid tumors.1
References:
1. Buonaiuto R, Neola G, Cecere SC, et al. Biomolecules. 2023;13(4):653. 2. Thau L, Gandhi J, Sharma S. Physiology, Cortisol. In: StatPearls. Treasure Island (FL): StatPearls Publishing; August 28, 2023. 3. Colombo N, Van Gorp T, Matulonis UA, et al. J Clin Oncol. 2023;41(30):4779-4789. 4. Veneris JT, Darcy KM, Mhawech-Fauceglia P, et al. Gynecol Oncol. 2017;146(1):153-160. 5. Greenstein AE, Hunt HJ. Oncotarget. 2021;12:1243-1255. 6. Greenstein AE, Hunt HJ. Int Immunopharmacol. 2023;120:110312. 7. Sang Y, Kong P, Zhang S, et al. Front Oncol. 2021;10:608722. 8. Mei W, Mei B, Chang J, et al. Front Pharmacol. 2024;15:1346745. 9. Dhanasekaran DN, Reddy EP. Oncogene. 2008;27(48):6245-6251. 10. Chen Y, Li N, Yang J, et al. Biochim Biophys Acta Mol Basis Dis. 2022;1868(12):166553. 11. Pedley R, Gilmore AP. Biol Chem. 2016;397(7):595-605. 12. Whitaker RH, Placzek WJ. Cells. 2019;8(4):346. 13. Liu Y, Ao X, Ding W, et al. Mol Cancer. 2018;17:104.
