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Published on: January 22, 2017
Protective effects of SS-31 against SDHB suppression-mitochondrial dysfunction-EndMT axis-modulated CBT sclerosis and
Hanfei Tang1, Chao Fang1, Song Xue1
1Department of Vascular Surgery, Institute of Vascular Surgery, Zhongshan Hospital, Fudan University Shanghai, China.
Abstract:
Sclerosis variant in carotid body tumor (CBT) is characterized by extensive stromal sclerosis, which results in an uncommon pattern of growth that closely resembles that of an invasive malignant neoplasm. However, the clinical significance and the mechanism remains unclear. In this study, we provide evidence that SS-31 exerts protective effects against SDHB suppression-mitochondrial dysfunction-EndMT axis-modulated CBT sclerosis and progression. In human CBT specimens, sclerosis extent was consistently related to decreased recurrence-, death-, systematic metastasis-, and major adverse event-free survival, decreased SDHB expression, and aggravated EndMT. In human umbilical vein endothelial cells (HUVECs), SDHB KD aggravated hypoxia-induced EndMT, mitochondrial dysfunction and metabolic switch, while SS-31 treatment could significantly attenuate these changes caused by SDHB KD and hypoxia. In patient-derived xenograft (PDX) mice models of CBT, we also observed increased tumor growth speed and extent of EndMT, mitochondrial dysfunction, and metabolic switch in sclerosing carotid body tumor (SCBT) group than in conventional carotid body tumor (CCBT) group. And treating with SS-31 could significantly retard SCBT progression by rescuing the mitochondrial dysfunction-induced EndMT. Altogether, these results show that SDHB suppression-mitochondrial dysfunction-EndMT axis is a critical part of the CBT sclerosis and progression, while mitochondria-targeted drug SS-31 exerts an inhibitive effect on the above-mentioned axis, which opens new strategies to prevent and treat malignancies of CBT.
Insights
The sclerosis variant in carotid body tumors (CBTs) involves a pathway of SDHB suppression, mitochondrial dysfunction, and EndMT. The drug SS-31 shows promise in inhibiting this axis, potentially treating CBT malignancies.
Area of Science:
- Oncology
- Mitochondrial Biology
- Cellular Biology
Background:
- Sclerosis variant in carotid body tumors (CBT) presents as extensive stromal sclerosis, mimicking invasive malignancy.
- The clinical significance and underlying mechanisms of CBT sclerosis remain poorly understood.
Purpose of the Study:
- To investigate the role of the SDHB suppression-mitochondrial dysfunction-EndMT axis in CBT sclerosis and progression.
- To evaluate the therapeutic potential of SS-31 against CBT sclerosis.
Main Methods:
- Analysis of human CBT specimens correlating sclerosis extent with clinical outcomes and molecular markers (SDHB, EndMT).
- In vitro studies using human umbilical vein endothelial cells (HUVECs) with SDHB knockdown (KD) and hypoxia, treated with SS-31.
- In vivo studies using patient-derived xenograft (PDX) mice models of sclerosing CBT (SCBT) and conventional CBT (CCBT), with and without SS-31 treatment.
Main Results:
- Sclerosis extent in human CBTs correlated with poorer survival, decreased SDHB expression, and increased EndMT.
- SDHB KD and hypoxia induced EndMT, mitochondrial dysfunction, and metabolic switch in HUVECs; SS-31 treatment attenuated these effects.
- SCBT models exhibited accelerated tumor growth, enhanced EndMT, mitochondrial dysfunction, and metabolic switch compared to CCBT models; SS-31 treatment inhibited SCBT progression by mitigating mitochondrial dysfunction-induced EndMT.
Conclusions:
- The SDHB suppression-mitochondrial dysfunction-EndMT axis is crucial for CBT sclerosis and progression.
- Mitochondria-targeted drug SS-31 demonstrates inhibitory effects on this axis, offering potential new strategies for CBT prevention and treatment.