n-3 polyunsaturated fatty acids abrogate mTORC1/2 signaling and inhibit adrenocortical carcinoma growth in vitro and in vivo

Abstract

n-3 polyunsaturated fatty acids (PUFAs) are essential for human health and have been reported to reduce the risk of cancer, inhibit the growth of various types of tumors both in vitro and in vivo, and affect adrenal function. However, their effects on adrenocortical carcinoma (ACC) are not known. In the present study, we demonstrated that docosahexenoic acid (DHA) inhibited ACC cell proliferation, colony formation and cell cycle progression, and promoted apoptosis. In addition, ectopic expression of fat-1, a desaturase that converts n-6 to n-3 PUFAs endogenously, also inhibited ACC cell proliferation. Moreover, supplementing n-3 PUFAs in the diet efficiently prevented ACC cell growth in xenograft models. Notably, implanted ACC cells were unable to grow in fat-1 transgenic severe combined immune deficiency mice. Further study revealed that exogenous and endogenous n-3 PUFAs efficiently suppressed both mTOR complex 1 (mTORC1) and mTORC2 signaling in ACC in vitro and in vivo. Taken together, our findings provide comprehensive preclinical evidence that n-3 PUFAs efficiently prevent ACC growth by inhibiting mTORC1/2, which may have important implications in the treatment of ACC.

The role of mTOR pathway as target for treatment in adrenocortical cancer

“…To the best of our knowledge, the effects of compounds targeting the mTORC1 and 2 complex in ACC cell lines have not been explored yet. A recent study reported that n-3 polyunsaturated fatty acids prevent ACC growth by inhibiting mTORC1/2 in preclinical models of ACCs, which suggests that both mTORC complexes might play a role in ACC cell proliferation (33). Another compound that was reported to inhibit ACC growth in preclinical models of ACCs is the dual PI3-kinase/mTOR inhibitor NVP-BEZ235 (34).…”

Stillbirth risk on fat-1 transgenic foetus of sheep caused by deregulated DNA methylation of imprinted genes

“…Subsequently, we noticed that the bio-functions of imprinted gene h19, igf2, igf2r, dlk1 and exogenous gene fat-1 were involved in developmental regulation. Fat-1 and h19 have roles in the negative regulation of cell proliferation (Gabory et al 2009;Liu, Zhou, et al 2016;Liu, Xu, et al 2016). In terms of foetal growth factor insulin-like growth factor 2 and its inhibitor insulin-like growth factor 2 receptor (DeChiara et al 1991;Lau et al 1994;Wang et al 1994), insulin-like growth factor systems are important to embryo development and organogenesis (Li et al 2007).…”

Algal Derived Functional Lipids and their Role in Promoting Health

“…Apoptosis was induced by DHA and, to a lesser extent by EPA (Sam, Ahangar, Nejati, & Habibian, 2016;Sun, Jia, Hou, Liu, & Gao, 2017;Wan, Fu, & Ababaikeli, 2016), but not by ALA (Mason, Klaire, Kharotia, Wiggins, & Thompson, 2015). Apoptosis was enhanced in DHA-treated cells through impairment of the activity of protein kinase Akt/PKB, p53 activation and increased caspase-3, caspase-9 and Bax pro-apoptotic enzyme levels or activity and decreased survival and Bcl-XL in various cancer cell lines and with DHA concentration ranging from 10 to 200 µM (Ahangar, Sam, Nejati, & Habibian, 2016;Chamras, Ardashian, Heber, & Glaspy, 2002;Han et al, 2016;J. Liu et al, 2016;Mason et al, 2015;M.…”