Klotho rewires cellular metabolism of breast cancer cells through alteration of calcium shuttling and mitochondrial activity

Shmulevich, Riva; Nissim, Tsipi Ben-Kasus; Wolf, Ido; Merenbakh-Lamin, Keren; Fishman, Daniel; Sekler, Israel; Rubinek, Tami

doi:10.1038/s41388-020-1313-5

Cited by 17 publications

(10 citation statements)

References 61 publications

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“…In this large-scale population-based database of NHANES, we explored comprehensively the effect of serum Klotho on cancer, and found regarding pan-cancer, there was no doubt that serum Klotho exerted a tumor suppressor For hormone-related cancer, prostate cancer, breast cancer, digestive and colon cancer, similar negative effect was observed with increased serum Klotho levels, although the tertiles of serum Klotho was not found to be associated with breast cancer risk, but this does not affect that there was consistent with previous histological evidence that Klotho is a tumor inhibitor. 28,29,30,31,32 A meta-analysis showed that the F allele of the F352 V polymorphism in Klotho gene protects against breast and ovarian cancer susceptibility and is associated with an overall risk of cancer in BRCA1 mutation carriers. 33 F352 V polymorphic mutation has been reported to alter protein function by affecting Klotho transport and catalytic activity in HeLa cells.…”

Section: Discussionmentioning

confidence: 99%

Association of serum Klotho levels with cancer and cancer mortality: Evidence from National Health and Nutrition Examination Survey

Qiao

Liu

et al. 2022

Cancer Medicine

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Background Klotho has both anticancer and hormone‐like functions. But the research on Klotho and cancer is mainly based on animal experiments and small‐scale clinical research, thus we explored the association between serum Klotho and cancer and cancer mortality based on the National Health and Nutrition Survey (NHANES). Methods Participants were employed from the NHANES 2007–2016, excluding pregnant, chronic renal insufficiency, and incomplete data of cancer questionnaire and serum Klotho level. The association of serum Klotho with cancer and mortality was analyzed by weighted Logistic regression, weighted Cox regression and competitive risk model, respectively. Correlations between serum Klotho and testosterone and estradiol levels were analyzed by Spearman correlation and restricted cubic spline respectively. Results We found Klotho had an inverse effect with risk of pan‐cancer (all p < 0.02), with each unit increase in Klotho (1ug/g creatinine) associated with a 0.9%–2.2% reduction in the risk of cancer, and higher levels showing a stronger negative association (all p‐trend <= 0.0005). Whereas, we did not observe any association between serum Klotho level with all‐cause mortality and cancer‐specific mortality (all p > 0.05). Then, stratified analysis found that people aged 60–79, female, overweight and non‐Hispanic whites or Mexican Americans were less likely to develop cancer. In addition, there was a strong nonlinear and linear positive correlation of Klotho with estradiol (p‐nonlinear = 0.0178) and testosterone only among male participants (β = −0.513, p = 0.0137), respectively. Conclusions We found an inverse association between serum Klotho and cancer, but without cancer mortality. And this effect may be partially mediated by estradiol and testosterone. Further prospective studies are needed to prove these findings.

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Section: Discussionmentioning

confidence: 99%

Association of serum Klotho levels with cancer and cancer mortality: Evidence from National Health and Nutrition Examination Survey

Qiao

Liu

et al. 2022

Cancer Medicine

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“…The expression of these factors is vital for maintaining the pluripotency of stem cells. As a longevity hormone, Klotho protects cells from oxidative stress; simultaneously, as a tumor suppressor, it inhibits the growth of cancer cells (17).…”

Section: Discussionmentioning

confidence: 99%

Metadichol, A natural ligand for expression of Yamanaka reprogramming factors in somatic and primary cancer cell lines

Raghavan¹

2022

Preprint

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The conversion of somatic cells back into induced pluripotent stem cells (iPSCs) or embryonic-like stem cells involves the introduction of four genes commonly called Yamanaka factors, i.e., Sox2, Oct4, Klf4, and c-Myc, into the cells. Because these genes and the viral vectors used to introduce them into cells have the potential to cause cancer, iPSC lines are not clinically useful. Most instances of direct reprogramming have achieved have been by the forced expression of defined factors using viral vectors. Here, we show that Metadichol® has the potential to generate iPSCs non-virally and may be helpful in clinical applications. Metadichol is a nanoformulation of long-chain alcohols derived from food. Quantitative real-time PCR (qRT-PCR) and western blotting showed that OCT4, SOX2, and Nanog are expressed when fibroblasts were treated with Metadichol at one picogram to 100 nanograms. Reverse-transcription PCR (RT-PCR) also revealed that OCT4, KLF4, Nanog, and Sox2 levels increased compared to controls by 4.01, 3.51 and 1.26, and 2.5-fold, respectively, in A549 cancer cells. In Colo-205 cells, OCT4, KLF4, and Sox2 were increased by 1.79, 13.17, and 2.25folds, respectively. Metadichol treatment with triple-negative primary breast cancer (HCAF-TNPBC) primary cancer cells led to multifold increases of OKSM factors by 19.6, 8.07, 2.45, and 6.91, folds increase in Metadichol concentration ranges one picogram to 100 nano grams. Metadichol is a natural product that induces the expression of Yamanaka factors needed for reprogramming and Klotho, an anti-aging gene, and curbs the expression of the TP53 gene, which is critical for reprogramming somatic cells into IPSCs.Metadichol increases endogenous vitamin C levels, leading to the efficient reprogramming of somatic cells into iPSCs. Metadichol is nontoxic and commercially available as a nutritional supplement. Thus, it can be directly tested in vivo in human subjects to confirm that cells can indeed be programmed into a state of induced pluripotency and cause the mitigation of disease conditions.

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“…However, this agent promoted the proliferation of highly invasive MDA-MB-231 cells which possessed AMPK-dependent EMT properties [ 200 ]. Alteration of the ATP/AMP ratio is a common mechanism that some modulators apply to activate AMPK [ 201 ]. Under glucose starvation stress, oligomycin A was found to induce AMPK phosphorylation in MCF-7 cells.…”

Section: Potential Ampk Modulators Of Chemical Synthesismentioning

confidence: 99%

Novel Anti-Cancer Products Targeting AMPK: Natural Herbal Medicine against Breast Cancer

et al. 2023

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Breast cancer is a common cancer in women worldwide. The existing clinical treatment strategies have been able to limit the progression of breast cancer and cancer metastasis, but abnormal metabolism, immunosuppression, and multidrug resistance involving multiple regulators remain the major challenges for the treatment of breast cancer. Adenosine 5′-monophosphate (AMP)-Activated Protein Kinase (AMPK) can regulate metabolic reprogramming and reverse the “Warburg effect” via multiple metabolic signaling pathways in breast cancer. Previous studies suggest that the activation of AMPK suppresses the growth and metastasis of breast cancer cells, as well as stimulating the responses of immune cells. However, some other reports claim that the development and poor prognosis of breast cancer are related to the overexpression and aberrant activation of AMPK. Thus, the role of AMPK in the progression of breast cancer is still controversial. In this review, we summarize the current understanding of AMPK, particularly the comprehensive bidirectional functions of AMPK in cancer progression; discuss the pharmacological activators of AMPK and some specific molecules, including the natural products (including berberine, curcumin, (−)-epigallocatechin-3-gallate, ginsenosides, and paclitaxel) that influence the efficacy of these activators in cancer therapy; and elaborate the role of AMPK as a potential therapeutic target for the treatment of breast cancer.

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Klotho rewires cellular metabolism of breast cancer cells through alteration of calcium shuttling and mitochondrial activity

Cited by 17 publications

References 61 publications

Association of serum Klotho levels with cancer and cancer mortality: Evidence from National Health and Nutrition Examination Survey

Association of serum Klotho levels with cancer and cancer mortality: Evidence from National Health and Nutrition Examination Survey

Metadichol, A natural ligand for expression of Yamanaka reprogramming factors in somatic and primary cancer cell lines

Novel Anti-Cancer Products Targeting AMPK: Natural Herbal Medicine against Breast Cancer

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