Solenopsin A and analogs exhibit ceramide-like biological activity

Main Article Content

Isabella Karlsson Xin Zhou Raquela Thomas Allorie T Smith Michael Y Bonner Pooja Bakshi Ajay K Banga J Phillip Bowen Ghassan Qabaja Shavon L Ford Matthew D Ballard Kimberly S Petersen Xuechen Li Guangping Chen Besim Ogretmen Jin Zhang E Blake Watkins Rebecca S Arnold Jack L Arbiser

Abstract

Background

(−)-Solenopsin A is a piperidine alkaloid that is a component of the venom of the fire antSolenopsis invicta. Previously, we have demonstrated that solenopsin exhibit anti-angiogenic activity and downregulate phosphoinositol-3 kinase (PI3K) in the p53 deficient renal cell carcinoma cell line 786-O. Solenopsin has structural similarities to ceramide, a major endogenous regulator of cell signaling and cancer therapy induced apoptosis.

Methods

Different analogs of solenopsin were synthesized in order to explore structure-activity relationships. The anti-proliferative effect of solenopsin and analogs was tested on six different cell lines, including three tumor cell lines, two normal cutaneous cell lines, and one immortalized hyperproliferative cell line. FRET-based reporters were used to study the affect of solenopsin and analogs on Akt activity and PDK1 activation and sucrose density gradient fractionation was performed to examine recruitment of PTEN to membrane rafts. Western-blotting was used to evaluate the affect of solenopsin and analogs on the Akt and the MAPK 44/42 pathways in three different tumor cell lines. Measurement of cellular oxygen consumption rate together with autophagy staining was performed to study mitochondrial function. Finally, the affect of solenopsin and analogs on ROS production was investigated.

Results

In this paper we demonstrate that solenopsin analogs with potent anti-proliferative effects can be synthesized from inexpensive dimethylpyridines. To determine whether solenopsin and analogs act as ceramide analogs, we examined the effect of solenopsin and analogs on two stereotypic sites of ceramide activity, namely at lipid rafts and mitochondria. We found that native solenopsin, (−)-solenopsin A, inhibits functional Akt activity and PDK1 activation in lipid rafts in a similar fashion as ceramide. Bothcisandtransanalogs of solenopsin reduce mitochondrial oxygen consumption, increase reactive oxygen, and kill tumor cells with elevated levels of Akt phosphorylation. However, only solenopsin induces mitophagy, like ceramide.

Conclusions

The requirements for ceramide induced mitophagy and inhibition of Akt activity and PDK1 activation in lipid rafts are under strict stereochemical control. The naturally occurring (−)-solenopsin A mimic some of the functions of ceramide and may be therapeutically useful in the treatment of hyperproliferative and malignant disorders of the skin, even in the presence of elevated levels of Akt.

Article Details

How to Cite
KARLSSON, Isabella et al. Solenopsin A and analogs exhibit ceramide-like biological activity. Vascular Cell, [S.l.], v. 7, n. 1, may 2015. ISSN 2045-824X. Available at: <http://vascularcell.com/index.php/vc/article/view/10.1186-s13221-015-0030-2>. Date accessed: 19 oct. 2017. doi: http://dx.doi.org/10.1186/s13221-015-0030-2.
Section
Original Research