Insulin Enhances Migration and Invasion in PCa.

[pjoshea13]

New Australian (+Canadian) cell study below [1].

As we know, most PCa cells use fatty acids for energy - not glucose. This is why fluorodeoxyglucose (FDG) PET scans are not generally used. However, we also know that diabetics have less PCa risk than non-diabetics. This suggests that a die-off of pancreatic beta cells, which secrete insulin, may be protective.

(As an alternative to becoming diabetic, we can control insulin levels by avoiding glucose spikes. Metformin is helpful in that regard.)

In the new study:

"Insulin increased invasiveness of PCa cells, ... activating key PCa cell plasticity mechanisms including gene changes consistent with epithelial-to-mesenchymal transition (EMT) and a neuroendocrine phenotype." Nasty!

The context of the study, though, is ADT:

"Androgen deprivation therapy (ADT) is the standard treatment for advanced prostate cancer (PCa), yet many patients relapse with lethal metastatic disease. With this loss of androgens, increased cell plasticity has been observed as an adaptive response to ADT. This includes gain of invasive and migratory capabilities, which may contribute to PCa metastasis. Hyperinsulinemia, which develops as a side-effect of ADT, has been associated with increased tumor aggressiveness and faster treatment failure. We investigated the direct effects of insulin in PCa cells that may contribute to this progression."

I must say that it is good to see some interest in insulin as something we need to target.

Note that the Triglycerides:HDL-Cholesterol ratio is a surrogate for insulin resistance. ("Resistance" means that we over-produce insulin in an attempt to overcome cellular resistance to it.)

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/313...

Front Endocrinol (Lausanne). 2019 Jul 17;10:481. doi: 10.3389/fendo.2019.00481. eCollection 2019.

Insulin Enhances Migration and Invasion in Prostate Cancer Cells by Up-Regulation of FOXC2.

Sarkar PL1, Lee W1, Williams ED1, Lubik AA2, Stylianou N1, Shokoohmand A1, Lehman ML1,2, Hollier BG1, Gunter JH1, Nelson CC1.

Author information

1

Queensland University of Technology (QUT), Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Faculty of Health, Translational Research Institute, Brisbane, QLD, Australia.

2

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.

Abstract

Androgen deprivation therapy (ADT) is the standard treatment for advanced prostate cancer (PCa), yet many patients relapse with lethal metastatic disease. With this loss of androgens, increased cell plasticity has been observed as an adaptive response to ADT. This includes gain of invasive and migratory capabilities, which may contribute to PCa metastasis. Hyperinsulinemia, which develops as a side-effect of ADT, has been associated with increased tumor aggressiveness and faster treatment failure. We investigated the direct effects of insulin in PCa cells that may contribute to this progression. We measured cell migration and invasion induced by insulin using wound healing and transwell assays in a range of PCa cell lines of variable androgen dependency (LNCaP, 22RV1, DuCaP, and DU145 cell lines). To determine the molecular events driving insulin-induced invasion we used transcriptomics, quantitative real time-PCR, and immunoblotting in three PCa cell lines. Insulin increased invasiveness of PCa cells, upregulating Forkhead Box Protein C2 (FOXC2), and activating key PCa cell plasticity mechanisms including gene changes consistent with epithelial-to-mesenchymal transition (EMT) and a neuroendocrine phenotype. Additionally, analysis of publicly available clinical PCa tumor data showed metastatic prostate tumors demonstrate a positive correlation between insulin receptor expression and the EMT transcription factor FOXC2. The insulin receptor is not suitable to target clinically however, our data shows that actions of insulin in PCa cells may be suppressed by inhibiting downstream signaling molecules, PI3K and ERK1/2. This study identifies for the first time, a mechanism for insulin-driven cancer cell motility and supports the concept that targeting insulin signaling at the level of the PCa tumor may extend the therapeutic efficacy of ADT.

KEYWORDS:

FOXC2; androgen deprivation; epithelial to mesenchymal transition (EMT); hyperinsulinemia; invasion; prostate cancer

PMID: 31379747 PMCID: PMC6652804 DOI: 10.3389/fendo.2019.00481

[Adam10]

Hi Patrick. Interesting post. Thank you.

Interested in your views on my conundrum. My endocrinologist is determined to have me take Glucophage (Metformin) which is usually used for diabetics even though I am not diabetic.

But my endo has followed my treatment for PCa (ablated in November 2018) and recent PSA reduced from 6.9 to 3.5 (range 0-5.2 as I’m over 60). My glucose (F) test result was 4.9 nmol/L (range 3.9-6.1) and my HbA1c was 5.3% (4.7-5.6% = non-diabetic).

So is my endo thinking of preventing return of my PCa (assuming it was fully ablated - watchful monitoring is ongoing) and preventing me becoming diabetic? I appreciate no one can know for sure.

Would metformin be useful for my PCa or is my endo over-focused with diabetes. I currently live in Middle East where diabetes is endemic.

I don’t want to take the Metformin based on what I’ve read about it and side effects. But should I reconsider?

[pjoshea13 in reply to Adam10]

Adam,

I'm just rushing out the door, but just to allay your concerns:

In 2016, it was the fourth-most prescribed medication in the United States, with more than 81 million prescriptions.

en.wikipedia.org/wiki/Metfo...

Not bad considering almost all were for diabetics.

Some do find it rough on the stomach, although I didn't.

I am on 4 x 500 mg (2,000 mg) daily.

Whatever the eventual dose, start with one 500 mg tablet. Stay with that a few weeks before adding another. & so on.

Best, -Patrick

[Adam10 in reply to pjoshea13]

Thank you for your reply Patrick.

Are you diabetic (hope you don’t mind me asking) or do you take Metformin to keep the PCa away?

I’m not diabetic so am wondering why my endo is so keen to get me taking Metformin medication which he says would be forever (for life).

My endo is aware of my PCa and has followed events. He put me on Nebido testosterone injections then stopped them immediately I was diagnosed PCa. I’m wondering if this is a PCa treatment?

My concern is it’s another medication I’m taking and I recall reading somewhere about the side effects of Glucophage (Metformin).

[pjoshea13 in reply to Adam10]

Adam,

At age 71, I am on a handful of prescriptions, including Metformin, but all off-label & requested for PCa.

Ironically, for those with PCa, it is the non-diabetics who need Metformin most. Basically, diabetes is diagnosed when one is unable to produce enough insulin, due to the die-off of beta cells. Non-diabetics with PCa include many pre-diabetics & many with the metabolic syndrome. But even men with no insulin resistance might benefit.

-Patrick

[Adam10 in reply to pjoshea13]

Patrick, thank you. That explains my Endo’s comments. He talked about Metformin being preventative.

It’s disheartening in some ways as I’d hoped I didn’t need it being non-diabetic.

It confused commentators on Thyroid UK - I’m hypothyroid with Hasimoto’s. They could see no need for my endo prescribing Metformin.

How does the Metformin help prevent PCa?

Adan

[pjoshea13 in reply to Adam10]

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[cashlessclay]

Patrick, I find this very interesting. . . "Note that the Triglycerides:HDL-Cholesterol ratio is a surrogate for insulin resistance."

My pre-diet trig/HDL was 247/37. My current reading, with diet, is trig/HDL = 52/62. As you can see, this is a powerful diet I'm using. That's why I can get it to work without supplements.

[pjoshea13 in reply to cashlessclay]

I contend that the ratio to aim for is ~1:1 which you have managed to do. 2nd prize would be <2:1. Your old ratio of 20:3 was pretty grim. It's an amazing turn around!

-Patrick

[Ahk1 in reply to cashlessclay]

Hi cashless,

I don’t think you take metformin? Do you?

[cashlessclay in reply to Ahk1]

No, have never taken Metformin.

[Ahk1 in reply to cashlessclay]

I thought so too. Since I failed to stop the psa rising And now went up to .74 using the dite, I am going to see my Uro on Monday and asking him for metformin. I see that lots of guys on here use it with good results and also dr. Myers recommends it very much. do you have any thoughts on this please? Thank you

[cashlessclay in reply to Ahk1]

Ahk1 . . . sorry, but I know almost nothing about using Metformin.