Metformin inhibits SUV39H1-mediated PCa migration

[pjoshea13]

New study below.

They keep finding new anti-PCa mechanisms for Metformin.

Note: SUV39H1 is a histone methyltransferase involved in cell migration (& therefore metastasis).

"SUV39H1 overexpression increased PCa migration, whereas SUV39H1 depletion suppressed PCa cell migration."

"There is a positive correlation between SUV39H1 expression and PCa pathological stages."

"... metformin reduced SUV39H1 to inhibit migration of PCa cells"

-Patrick

ncbi.nlm.nih.gov/pubmed/284...

Oncogenesis. 2017 May 1;6(5):e324. doi: 10.1038/oncsis.2017.28.

Metformin inhibits SUV39H1-mediated migration of prostate cancer cells.

Yu T1,2,3, Wang C4, Yang J3, Guo Y3, Wu Y1,2,3,5, Li X3,6,7.

Author information

1

Institute of Gene Engineered Animal Models for Human Diseases, Dalian Medical University, Dalian, China.

2

Institute of Integrative Medicine, Dalian Medical University, Dalian, China.

3

Department of Basic Science and Craniofacial Biology, New York University College of Dentistry (NYUCD), New York, NY, USA.

4

Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.

5

The Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China.

6

Department of Urology, New York University Langone Medical Center, New York, NY, USA.

7

Perlmutter Cancer Institute, New York University, Langone Medical Center, New York, NY, USA.

Abstract

Prostate cancer (PCa) is a leading cause of cancer-related death among men, largely due to incurable distant metastases. Metformin, the most common used anti-type-2 diabetes medicine, has been linked to reduced cancer risk and better diagnosis. We found that metformin was able to inhibit PCa cell migration, which correlates with tumor metastatic capability. The pathogenesis and progression of tumors are closely related to dysregulated gene expression in tumor cells through epigenetic alterations such as DNA methylation and histone modifications. We found that the level of SUV39H1, a histone methyltransferase of H3 Lys9, was reduced in metformin-treated PCa cells in a time-dependent manner. SUV39H1 overexpression increased PCa migration, whereas SUV39H1 depletion suppressed PCa cell migration. There is a positive correlation between SUV39H1 expression and PCa pathological stages. We further showed that both metformin treatment and SUV39H1 knockout in PCa cells can reduce integrin αV and β1 proteins, as well as their downstream phosphorylated focal adhesion kinase (FAK) levels, which is essential for functional adhesion signaling and tumor cell migration. Taken together, metformin reduced SUV39H1 to inhibit migration of PCa cells via disturbing the integrin-FAK signaling. Our study suggests SUV39H1 as a novel target to inhibit PCa cell migration.

PMID: 28459432 DOI: 10.1038/oncsis.2017.28

[jsatt11]

Thanks Patrick,

Many here probably know enough to speculate and what steps could be taken to bring this discovery to fruition for advanced metastatic prostate cancer usage. But for many others of us could you speculate what these steps might be. And how long would they take?

Thanks for this and all your posts.

[pjoshea13 in reply to jsatt11]

As a Metformin user, I find it comforting to see the various ways that Metformin may act. However, only human studies matter. Bear in mind that most of those involve diabetics.

There is a Swiss study that used 2,000 mg/day. Four 500 mg pills in a divided dose. The population was 44 non-diabetic men with CRPC. That is a tough population to treat. Note that CRPC men are likely to be near-diabetic.

"The primary end point was the absence of disease progression at 12 wk."

"Thirty-six percent of patients were progression-free at 12 wk, 9.1% were progression-free at 24 wk, and in two patients a confirmed ≥ 50% prostate-specific antigen (PSA) decline was demonstrated. In 23 patients (52.3%) we observed a prolongation of PSA DT after starting metformin."

If it can slow progression in CRPC cases, what can it do in non-CRPC cases? Perhaps it should be prescribed at diagnosis - even in active surveillance cases. & in men at high risk for PCa? & in men over 50, say, with symptoms of the metabolic syndrome?

& it costs pennies a day.

"Treatment with metformin is safe in nondiabetic patients, and it yields objective PSA responses and may induce disease stabilization. The activity of metformin in PCa, along with its low cost, favorable toxicity profile, and positive effect on metabolic parameters, suggests that further investigation of metformin as therapy for patients with PCa is of interest."

ncbi.nlm.nih.gov/pubmed/244...

My posts describe various ways in which we might increase survival odds. Metformin may be the most important agent in my overall strategy, but a single agent is unlikely to give optimal results.

-Patrick

[Dan59]

Thanks Patrick, My nonfasting glucose was 162 today,That may be enough to get some metformin, but that was after 24 mg dexamethasone for chemo in past 36 hrs. 5th chemo went well today, scans showed significant (to me) reduction, psa not in yet, doing the happy dance today

[Sisira]

Thank you very much Patrick for this finding. The wonderful effect of this commonly used and cheap drug to control Type-2 Diabetics. Surely the multinational pharmaceutical companies and those oncologists who are their cronies will not recommend such cheap drugs for cancer treatment! Do you have any idea about the daily dosage of Metformin that can yield this benefit on PCa?

Sisira

[pjoshea13 in reply to Sisira]

Sisira,

See my response to jsatt11, above. That's why I use 2,000 mg/day.

-Patrick

[enzo1]

Hi, I'm also looking for "something else" to treat this disease, but ...

medicalxpress.com/news/2017...

... metformin seems not to be useful. Is it?

[Sisira in reply to enzo1]

This seems to be a synergy issue as a combination drug when used with Docetaxel.The indications of Metformin explained in Patrick's post impact on different other aspects. This is my personal evaluation and certainly I appreciate your having provided a link to look at Metformin more seriously in the treatment of PCa from a different angle. Thanks.

Sisira

[pjoshea13 in reply to enzo1]

enzo1,

The study conclusion:

"Metformin use during docetaxel chemotherapy did not significantly improve prostate cancer specific or overall survival in diabetic patients with metastatic castration resistant prostate cancer."

There is no mention of dosage, which, I believe, might be as low as 500 mg in diabetics.

See my response to jsatt11, above. The study I cite is why I use 2,000 mg/day.

In the Canadian study, there is no mention of Metformin in non-diabetics. That's because it is not an intervention study. I'd like to see the full text, but it seems to be a lazy study. They are comparing diabetics who use Metformin against diabetics who don't. What are the latter using to control diabetes? Metformin is the first line of treatment & Metformin use often continues after its action is no longer sufficient. But some men do not tolerate it. It might be useful to know more about the two populations.

The dose might be an issue, but the duration could be important too. The importance of Metformin is more apparent over time.

The Swiss study is clean. Dr. Myers raves about it. I like it because it finds success in non-diabetics who are at an advance stage, but have not used Taxotere. Would similar results have occurred if they were all using Taxotere? I can't say.

-Patrick

[enzo1 in reply to pjoshea13]

You are right ... It's difficult for me, to read and understand eveything. My english is not good enough; I need time and often I'm not sure to understand exactly everything. So I appreciate your post. About one thing I can be sure. Yust 5 months after docetaxel, next week I'm going to begin with cabazitaxel, because of bone meths' progression; I'll tell to my onchologist about metformin, and she'll tell me: guidelines don't speak about metformin, why? What can I tell her?

[pjoshea13 in reply to enzo1]

Print out the Swiss study & hand over a copy.

[rococo]

Horay another plus for metformin. My pharmasist thinks its a wonder drug. Thanks Patrick.