Mineralocorticoid and glucocorticoid receptors as novel targets in breast and liver cancer therapies

Abstract

Cell signaling is a complex phenomenon and is maintained through intertwined signal transmissions within and in-between the cells. Anti-cancer therapies are often challenged by this fact due to crosstalk-associated activation of alternative survival routes. Hence, development of new treatment strategies and identification of novel prognostic markers depends on in-depth knowledge on cell signaling routes altered in cancer and possible crosstalk paths. Herein, mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) signaling, two closely related members of steroid receptor hormone family, and their possible crosstalk were studied across breast and liver cancer cell lines. In breast cancer cell lines, estrogen responsive and MR expressing T47D was used in order to study possible crosstalk among Estrogen receptor (ER) and MR. MR-GR ligand aldosterone (ALDO) and ER ligand estrogen (E2) administered to breast cancer cells alone and in combination and, MR, ER and GR and their downstream signaling members were studied employing qRT-PCR and Western blot assays. Furthermore, ALDO, E2, ALDO-E2 hormone administrations were also used for cell viability assessments. Our results implied possible interactions of ALDO-E2 signaling at the level of cell viability, and at mRNA levels of progesterone receptor. In liver cancer cell lines, MR and GR was investigated as targets of a novel treatment. Liver cancer subtype hepatocellular carcinoma (HCC) has high mortality rate with limited treatment options. Multi-kinase inhibitor Sorafenib (SFB) with mild effectivity is most known systemic therapy against HCC. To potentiate the effectiveness of SFB and overcome to the crosstalk associated limitations, combinatorial drug treatment approach targeting multiple signaling modalities has been adopted in literature. Previously in our lab, SFB was combined with repurposed anti-psychotic drug TFP as a novel combinatorial treatment against hepatocellular carcinoma (HCC) and liver cancer cell lines. Cellular viability was synergistically reduced by SFB-TFP in HCC cell line Hep3B, while antagonistic effects on viability in SkHep1 was apparent. Herein, two liver cancer cell lines Hep3B and SkHep1, were used in comparison to unravel mechanism of action of SFB-TFP combination at the protein level. Apoptosis, cell cycle, PI3K/AKT/mTOR and MAPK pathways were investigated in addition to MR and GR. Our results revealed several markers indicating success of drug combinations and targeted pathways at protein level which needs to be pursued further.