Could S. pombe be a source of TSC2 for treating conditions linked to androgen-induced mTORC1 over-activity?

In the past few months, I've read a lot about the mTOR (mTORC1 and mTORC2) pathways. They are vital to life, but inappropriate activation of them is related to many conditions. Two androgen-related ailments in which mTORC1 over-activation appears to be involved are acne (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015761/, https://onlinelibrary.wiley.com/doi/full/10.1111/exd.12885) and prostate cancer (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499189/). There are androgen-blocking medications available to treat acne and prostate cancer, but the side effects are sometimes quite unpleasant (https://www.dermnetnz.org/topics/anti-androgen-therapy/).

There is a complex that is supposed to be formed by the proteins TSC1 and TSC2 which is then supposed to decrease mTORC1 activity (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735030/). A 2014 study reported that androgen causes a shorter version of TSC2 to be translated which cannot properly form a complex with TSC1 and is ineffective at decreasing mTORC1 activity:

TSC2 (Tuberous sclerosis complex 2) is an important tumour suppressor gene, mutations within which are linked to the development of tuberous sclerosis and implicated in multiple tumour types. TSC2 protein complexes with TSC1 and blocks the ability of the Rheb (Ras homolog enriched in brain) GTPase to activate mTOR (mammalian target of rapamycin), a crucial signal transducer which regulates protein synthesis and cell growth. Here, we report the characterisation of a novel isoform of TSC2 which is under direct control of the ligand-activated androgen receptor. TSC2 isoform A (TSC2A) is derived from an internal androgen-regulated alternative promoter and encodes a 508-amino acid cytoplasmic protein corresponding to the C-terminal region of full-length TSC2, lacking the interaction domain for TSC1 and containing an incomplete interaction domain required for Rheb inactivation. Expression of TSC2A is induced in response to androgens and full-length TSC2 is co-ordinately down-regulated, indicating an androgen-driven switch in TSC2 protein isoforms. In contrast to the well-characterised suppressive efect on cell proliferation of full-length TSC2 protein, both LNCaP and HEK293 cells over-expressing TSC2 isoform A proliferate more rapidly (measured by MTT assays) and have increased levels of cells in S-phase (measured by both Edu staining and FACS analysis). Our work indicates, for the first time, a novel role for this well-known tumour suppressor gene, which encodes an activator of cell proliferation in response to androgen stimulation.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3960195/

What to do when the body won't translate the correct form of a protein? I started searching for another source of TSC2. Other mammals make it, but I suspect the necessary cooking and sterilizing processes would damage the TSC2 we obtain from other mammals' secretions and tissues.

I found another TSC2 source: it's the mostly ignored (except by researchers, who use it all the time) wild yeast called Schizosaccharomyces pombe (S. pombe). S. pombe, unlike the Saccharomyces cerevisiae yeast used in nearly all brewing and baking (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735030/), contains versions of TSC1 and TSC2 that are similar to the human versions (http://www.jbc.org/content/279/13/12706.long).

Guess where S. pombe often shows up? In the making of hard apple cider and its subsequent product, apple cider vinegar. S. pombe is a wild yeast that is frequently found on grape and apple skins; given enough sugar, it multiplies very quickly. Have you ever wondered why apple cider vinegar--and not other kinds of vinegar--is so widely recommended as a home remedy for a vast variety of ailments? I have. I've heard it so often that my immediate reaction is to start rolling my eyes when I see it popping up in my search results yet again. Nevertheless, while the placebo effect is real, I can't easily disregard so many anecdotes claiming that apple cider vinegar has helped them. However, I can accept that some apple cider vinegar fermentations include more S. pombe yeast than others and so contain more proteins from S. pombe that are uniquely able to help with mTORC1-related conditions; I can thus accept that non-equivalent fermentations lead to non-reproducible results from raw apple cider vinegar.

I'd love to know whether a researcher has tested TSC2 from disrupted S. pombe on something fairly simple (yet annoyingly difficult to treat) like acne. Any takers out there on the global web? If it works, you might have harnessed a way to help treat prostate cancer, too. Not a bad use for your extra pombe.... (In the meantime, I've got a jar of water, sugar, and cut apples sitting on my counter in hopes that the pombe fairy will visit me.)