Sulforaphane induces differential modulation of mitochondrial biogenesis and dynamics in normal cells and tumor cells

Negrette-Guzmán, Mario; Huerta-Yépez, Sara; Vega, Mario I.; León-Contreras, Juan Carlos; Hernández-Pando, Rogelio; Medina-Campos, Omar Noel; Rodríguez, Estéban M.; Tapia, Edilia; Pedraza‐Chaverrí, José

doi:10.1016/j.fct.2016.12.020

Cited by 47 publications

(36 citation statements)

References 48 publications

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“…In addition, some cell lines undergo cell death if they cannot be prevented with antioxidants . In addition, the crucial role of mitochondria in cell death has been widely accepted, and radiotherapy‐induced oxidative stress plays an important role in the death of cell mitochondria …”

Section: Discussionmentioning

confidence: 99%

“…17,18 In addition, the crucial role of mitochondria in cell death has been widely accepted, 19 and radiotherapy-induced oxidative stress plays an important role in the death of cell mitochondria. 20 However, the mechanism underlying this process and the factors involved remain unclear. Some proteins, such as GSK-3β, might play crucial roles in oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

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IL‐8 protects prostate cancer cells from GSK‐3β‐induced oxidative stress by activating the mTOR signaling pathway

Sun

Jin

et al. 2019

The Prostate

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Introduction Both oxidative stress and inflammation play important roles in prostate cancer cell apoptosis or proliferation; however, the mechanisms underlying these processes remain unclear. Thus, we selected interleukin‐8 (IL‐8) as the bridge between inflammation and cancer cell oxidative stress‐induced death and aimed to confirm its connection with mTOR and Glycogen synthase kinase‐3 beta (GSK‐3β). Methods We overexpressed GSK‐3β and observed its effect on reactive oxygen species (ROS) and oxidative stress‐induced cell death. IL‐8 was then upregulated or downregulated to determine its impact on preventing cell damage due to GSK‐3β‐induced oxidative stress. In addition, we overexpressed or knocked down mTOR to confirm its role in this process. Real‐time PCR, Western blotting, transcription, Cell Counting Kit 8 (CCK‐8), and flow cytometry analyses were performed in addition to the use of other techniques. Results IL‐8 promotes prostate cancer cell proliferation and decreases apoptosis, whereas GSK‐3β activates the caspase‐3 signaling pathway by increasing ROS and thereby induces oxidative stress‐mediated cell death. In addition, mTOR can also decrease activation of the caspase‐3 signaling pathway by inhibiting GSK‐3 and thus decreasing ROS production. Moreover, the inhibitory effect of IL‐8 on GSK‐3β occurs through the regulation of mTOR. Conclusion The results of this study highlight the importance of GSK‐3β, which increases the production of ROS and thereby induces oxidative stress in tumor cells, whereas IL‐8 and mTOR attenuate oxidative stress to protect prostate cancer cells through inhibition of GSK‐3β.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

IL‐8 protects prostate cancer cells from GSK‐3β‐induced oxidative stress by activating the mTOR signaling pathway

Sun

Jin

et al. 2019

The Prostate

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“…SFN showed broad and complex effects on DNA methylation profiles in both normal and cancerous prostate epithelial cells 31 and regulated the Nrf2/ARE signalling pathway differently in human untransformed epithelial colon cells when compared to colorectal cancer cells 32,33 . Negrette-Guzman et al demonstrated SFN modulates mitochondrial dynamics differentially in normal and cancer cells 34 . The transcriptional response to SFN on cell cycle related genes was dependent on the cell line and presumably the state of cancer progression 35,36 .…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Antioxidant effects of sulforaphane in human HepG2 cells and immortalised hepatocytes

Liu

Wang

Tang

et al. 2019

Food and Chemical Toxicology

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Sulforaphane (SFN) has shown anti-cancer effects in cellular and animal studies but its effectiveness has been limited in human studies. Here, the effects of SFN were measured in both human hepatocyte (HHL5) and hepatoma (HepG2) cells. Results showed that SFN inhibited cell viability and induced DNA strand breaks at high doses (≥ 20 µM). It also activated the nuclear factor (erythroidderived 2)-like 2 (Nrf2), and increased intracellular glutathione (GSH) levels at 24 hours. Pretreatment with a low dose SFN (≤5 µM) protected against hydrogen peroxide (H 2 O 2)-induced cell damage. High doses of SFN were more toxic towards HHL5 compared to HepG2 cells; the difference is likely due to the disparity in the responses of Nrf2-driven enzymes and-GSH levels between the two cell lines. In addition, HepG2 cells hijacked the cytoprotective effect of SFN over a wider dose range (1.25-20 µM) compared to HHL5. Manipulation of levels of GSH and Nrf2 in HepG2 cells confirmed that both molecules mediate the protective effects of SFN against H 2 O 2. The non-specific nature of SFN in the regulation of cell death and survival could present undesirable risks, i.e. be more toxic to normal cells, and cause chemo-resistance in tumor cells. These issues should be addressed in the context for cancer prevention and treatment before large scale clinical trials are undertaken.

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“…To explain why the AZ + SFN combination would be most effective as a therapeutic regimen we offer the following. Recent studies support SFN as a potent antitumor agent against multiple signaling pathways in diverse cancers and targeting of mitochondrial functions where normal cells are protected [45][46][47][48][49][50]. Expression of carbonic anhydrase IX (CAIX) is highly relevant to rapidly growing and aggressive tumor cells adapting to the acidic microenvironment in rapidly growing tumors in order to maintain a more intracellular physiological pH, and thus inhibitors of CAIX can potently inhibit tumor cell viability [51,52].…”

Section: Discussionmentioning

confidence: 99%

Human bronchial carcinoid tumor initiating cells are targeted by the combination of acetazolamide and sulforaphane

et al. 2019

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Background Bronchial carcinoids are neuroendocrine tumors that present as typical (TC) and atypical (AC) variants, the latter being more aggressive, invasive and metastatic. Studies of tumor initiating cell (TIC) biology in bronchial carcinoids has been hindered by the lack of appropriate in-vitro and xenograft models representing the bronchial carcinoid phenotype and behavior. Methods Bronchial carcinoid cell lines (H727, TC and H720, AC) were cultured in serum-free growth factor supplemented medium to form 3D spheroids and serially passaged up to the 3rd generation permitting expansion of the TIC population as verified by expression of stemness markers, clonogenicity in-vitro and tumorigenicity in both subcutaneous and orthotopic (lung) models. Acetazolamide (AZ), sulforaphane (SFN) and the AZ + SFN combination were evaluated for targeting TIC in bronchial carcinoids. Results Data demonstrate that bronchial carcinoid cell line 3rd generation spheroid cells show increased drug resistance, clonogenicity, and tumorigenic potential compared with the parental cells, suggesting selection and expansion of a TIC fraction. Gene expression and immunolabeling studies demonstrated that the TIC expressed stemness factors Oct-4, Sox-2 and Nanog. In a lung orthotopic model bronchial carcinoid, cell line derived spheroids, and patient tumor derived 3rd generation spheroids when supported by a stroma, showed robust tumor formation. SFN and especially the AZ + SFN combination were effective in inhibiting tumor cell growth, spheroid formation and in reducing tumor formation in immunocompromised mice. Conclusions Human bronchial carcinoid tumor cells serially passaged as spheroids contain a higher fraction of TIC exhibiting a stemness phenotype. This TIC population can be effectively targeted by the combination of AZ + SFN. Our work portends clinical relevance and supports the therapeutic use of the novel AZ+ SFN combination that may target the TIC population of bronchial carcinoids.

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Sulforaphane induces differential modulation of mitochondrial biogenesis and dynamics in normal cells and tumor cells

Cited by 47 publications

References 48 publications

IL‐8 protects prostate cancer cells from GSK‐3β‐induced oxidative stress by activating the mTOR signaling pathway

IL‐8 protects prostate cancer cells from GSK‐3β‐induced oxidative stress by activating the mTOR signaling pathway

Antioxidant effects of sulforaphane in human HepG2 cells and immortalised hepatocytes

Human bronchial carcinoid tumor initiating cells are targeted by the combination of acetazolamide and sulforaphane

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