The role of reproductive hormones in epithelial ovarian carcinogenesis

Gharwan, Helen; Bunch, Kristen; Annunziata, Christina M.

doi:10.1530/erc-14-0550

Cited by 37 publications

(47 citation statements)

References 289 publications

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“…Epidemiological studies indicate that hormones and reproductive factors play important roles in the pathogenesis of ovarian cancer [3][4][5]. In addition, previous studies postulated that chemicals in the environment, including endocrine disruptors, also interfere with the actions of steroid sex hormones, and contribute to the development of ovarian cancer [6,7].…”

Section: Introductionmentioning

confidence: 99%

A new SIRT1 inhibitor, MHY2245, induces autophagy and inhibits energy metabolism via PKM2/mTOR pathway in human ovarian cancer cells

Tae¹,

Son²,

Lee³

et al. 2020

Int. J. Biol. Sci.

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Ovarian cancer is a common gynecological cancer that is found worldwide. Class III histone deacetylase (HDAC) inhibitors, a new class of anticancer agents, induce autophagy in various human cancer cells. The aim of the present study was to investigate the antitumor activity of MHY2245, a new synthetic SIRT inhibitor, on human ovarian cancer cells. We found that MHY2245 exhibited potent cytotoxicity to SKOV3 cells in a time-and concentration-dependent manner. The cytotoxicity of MHY2245 (IC 50 =0.32 µM) was higher than that of doxorubicin (DOX, IC 50 =1.38µM) against SKOV3 cells. MHY2245 significantly inhibited SIRT1 enzyme activity, reduced the expression of SIRT1, increased cell cycle arrest at G 2 /M phase, and induced apoptotic cell death in SKOV3 cells via expression of cytochrome c, cleaved-PARP, cleaved caspase-3, and Bax. This might be associated with blocking of the pyruvate kinase M2 (PKM2)/mTOR pathway. MHY2245 also inhibited tumor growth and reduced tumor size when SKOV3 cells were transplanted into nude mice. Our results indicate that MHY2245 exerts antitumor activity against ovarian cancer cells by blocking the PKM2/mTOR pathway. We suggest that MHY2245 is a promising anticancer agent that disrupts ovarian cancer cell metabolism.

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Section: Introductionmentioning

confidence: 99%

A new SIRT1 inhibitor, MHY2245, induces autophagy and inhibits energy metabolism via PKM2/mTOR pathway in human ovarian cancer cells

Tae¹,

Son²,

Lee³

et al. 2020

Int. J. Biol. Sci.

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show abstract

“…Another causative links between aging of endocrine system and ovarian cancer include the time-dependent accumulation of preneoplastic lesions within the ovary, plausibly combined with the depletion of ovarian follicles. 4, 5, 6 …”

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confidence: 99%

Senescent peritoneal mesothelium creates a niche for ovarian cancer metastases

et al. 2016

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Although both incidence and aggressiveness of ovarian malignancy rise with age, the exact reason for this tendency, in particular the contribution of senescent cells, remains elusive. In this project we found that the patient's age determines the frequency of intraperitoneal metastases of ovarian cancer. Moreover, we documented that senescent human peritoneal mesothelial cells (HPMCs) stimulate proliferation, migration and invasion of ovarian cancer cells in vitro, and that this effect is related to both the activity of soluble agents released to the environment by these cells and direct cell-cell contact. The panel of mediators of the pro-cancerous activity of senescent HPMCs appeared to be cancer cell line-specific. The growth of tumors in a mouse peritoneal cavity was intensified when the cancer cells were co-injected together with senescent HPMCs. This effect was reversible when the senescence of HPMCs was slowed down by the neutralization of p38 MAPK. The analysis of lesions excised from the peritoneum of patients with ovarian cancer showed the abundance of senescent HPMCs in close proximity to the cancerous tissue. Collectively, our findings indicate that senescent HPMCs which accumulate in the peritoneum in vivo may create a metastatic niche facilitating intraperitoneal expansion of ovarian malignancy.

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“…TgfβR3 acts as a Tgfβ protein superfamily co-receptor (30). Progesterone decreases expression of TgfβR1 and increases TgfβR2/R3 on normal epithelial cells and that might explain the protective effect of progesterone against ovarian cancer (31). TgfβR3 suppresses ovarian tumorigenesis and its expression is reduced or lost on malignant ovarian epithelium (32).…”

Section: Discussionmentioning

confidence: 99%

Role of Platelet-Derived Tgfβ1 in the Progression of Ovarian Cancer

Hisamatsu

Haemmerle

et al. 2017

Clinical Cancer Research

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Purpose Transforming growth factor β1 (Tgfβ1) plays an important role in cancer. Most of Tgfβ1 in plasma is from platelets, thus we studied whether platelet Tgfβ1 has any role in the progression of ovarian cancer, and whether this role is limited to metastasis or also involves the growth of primary tumors. Experimental Design We compared the growth of murine ovarian cancer cell-induced tumors in platelet-specific Tgfβ1 deficient mice and wild-type mice. Using resected tumor nodules, we studied the effect of platelet Tgfβ1 on neoangiogenesis and on platelet extravasation into tumors. To investigate the effect of Tgfβ1 at different stages of ovarian cancer, we reduced expression of Tgfβ1 receptor (its TgfβR1 component) in tumors at different time points after injection of cancer cells, and compared the final tumor size. Results Lack of platelet Tgfβ1 in mice reduced tumor growth, neoangiogenesis, and platelet extravasation. Ovarian cancer tumors in platelet-specific Tgfβ1 deficient mice reached less than half of their size in wild-type littermates. Knockdown of TgfβR1on cancer cells in the first 2 weeks after their injection reduced tumor growth, but was less effective if initiated after 3 weeks. Conclusions We showed that platelet Tgfβ1 increased the growth of primary tumors in murine models of ovarian cancer. We also showed that inhibition of TgfβR1 is more effective in reducing the growth of ovarian cancer if initiated earlier. Our results supported a therapeutic benefit in preventing platelet activation, degranulation, and release of Tgfβ1 in ovarian cancer.

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The role of reproductive hormones in epithelial ovarian carcinogenesis

Cited by 37 publications

References 289 publications

A new SIRT1 inhibitor, MHY2245, induces autophagy and inhibits energy metabolism via PKM2/mTOR pathway in human ovarian cancer cells

A new SIRT1 inhibitor, MHY2245, induces autophagy and inhibits energy metabolism via PKM2/mTOR pathway in human ovarian cancer cells

Senescent peritoneal mesothelium creates a niche for ovarian cancer metastases

Role of Platelet-Derived Tgfβ1 in the Progression of Ovarian Cancer

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