Activation of SphK1 by adipocytes mediates epithelial ovarian cancer cell proliferation

et al. 2021

Front. Oncol.

Ovarian cancer is the eighth most commonly diagnosed cancer among women worldwide. Even with the development of novel drugs, nearly one-half of the patients with ovarian cancer die within five years of diagnosis. These situations indicate the need for novel therapeutic agents for ovarian cancer. Increasing evidence has shown that hypoxia-inducible factor-1α(HIF-1α) plays an important role in promoting malignant cell chemoresistance, tumour metastasis, angiogenesis, immunosuppression and intercellular interactions. The unique microenvironment, crosstalk and/or interaction between cells and other characteristics of ovarian cancer can influence therapeutic efficiency or promote the disease progression. Inhibition of the expression or activity of HIF-1α can directly or indirectly enhance the therapeutic responsiveness of tumour cells. Therefore, it is reasonable to consider HIF-1α as a potential therapeutic target for ovarian cancer. In this paper, we summarize the latest research on the role of HIF-1α and molecules which can inhibit HIF-1α expression directly or indirectly in ovarian cancer, and drug clinical trials about the HIF-1α inhibitors in ovarian cancer or other solid malignant tumours.

Section: Adipocytesmentioning

confidence: 99%

HIF-1α Is a Rational Target for Future Ovarian Cancer Therapies

et al. 2021

Front. Oncol.

“…However, the exact mechanism of the adipocyte-induced c-Myc expression is not yet clear. c-Myc could be targeted by other adipocyte-regulated pathways, such as the SphK1 [ 16 , 48 ], AKT [ 25 , 49 ], and ERK [ 23 , 50 ] pathways. In addition, c-Myc could also be activated by adipocyte-secreted factors, such as estrogen [ 51 , 52 ], interleukin-6 [ 3 , 53 ], and interleukin-8 [ 3 , 54 ].…”

Section: Discussionmentioning

confidence: 99%

“…SphK1, which was overexpressed in EOC tissue [ 14 ], was inversely correlated with overall survival (OS) in EOC patients [ 15 ]. Moreover, elevated SphK1 levels were associated with EOC growth [ 16 ], metastasis [ 14 ], angiogenesis [ 17 ], and chemotherapeutic resistance [ 18 ]. Furthermore, knockout of SphK1 significantly blocked the EOC progression [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Activation of SphK2 contributes to adipocyte-induced EOC cell proliferation

Dai

et al. 2022

Open Medicine

Self Cite

Epithelial ovarian cancer (EOC) is the leading cause of deaths due to cancer in women. Adipocytes have been suggested to play a key role in the stimulation of EOC growth. However, the mechanisms underlying the adipocyte-induced EOC proliferation remain undefined. Here, we provide the first evidence that adipocytes induce the activation of sphingosine kinase (SphK) 2 in EOC, which represents a novel pathway that mediates the adipocyte-induced EOC growth. SphK2 inhibition in EOC cells led to a remarkable inhibition of the adipocyte-induced cell proliferation. Moreover, the adipocyte-induced SphK2 activation in EOC cells was extracellular signal-regulated protein kinases (ERK) dependent. Furthermore, silencing SphK2 in EOC significantly inhibited the adipocyte-induced expression of phospho-ERK and c-Myc, two crucial players in EOC growth. Collectively, the current study unraveled a previously unrecognized role of SphK2 in the adipocyte-induced growth-promoting action in EOC, suggesting a novel target for EOC treatment.

“…We previously showed that SphK1 was over-expressed in EOC tissue and was involved in EOC growth and angiogenesis [ 5 – 7 ]. We recently found adipocytes could activate SphK1 in EOC cells [ 6 ]. In this work, we tested the role of SphK1 in EOC metastasis induced by adipocyte-rich niche.…”

Section: To the Editormentioning

confidence: 99%

“…SphK1 catalyzes the phosphorylation of sphingosine to produce sphingosine-1-phosphate (S1P), which can act through S1P receptor (S1PR) pathway and intracellular pathway [4]. We previously showed that SphK1 was over-expressed in EOC tissue and was involved in EOC growth and angiogenesis [5][6][7]. We recently found adipocytes could activate SphK1 in EOC cells [6].…”

Section: To the Editormentioning

confidence: 99%

Sphingosine kinase 1 contributes to the metastatic potential of epithelial ovarian cancer to the adipocyte-rich niche

et al. 2022

Exp Hematol Oncol

Self Cite

Unlike many solid tumors, epithelial ovarian cancer (EOC) has a clear metastatic predilection to the adipocyte-rich niche, especially the omentum. However, the underlying mechanism driving this process remains incomplete. Here we show that SphK1 is over-expressed in omental metastases compared with ovarian primary tumors in EOC patients. In vitro, inhibition of SphK1 suppressed the metastatic ability of EOC induced by adipocytes. In vivo, blockage of SphK1 could attenuate the omental metastasis of EOC. Importantly, SphK1 modulates adipocyte-induced E/N-cadherin switch through Twist1, a key process in EOC metastasis. Our study reveals a previously unrecognized role of SphK1 in modulating the metastatic tropism of EOC to the adipocyte-rich niche, suggesting a new target for EOC therapy.