Mitochondrial protein LETM1 and its-mediated CTMP are potential therapeutic targets for endometrial cancer

Abstract

Leucine zipper/EF hand-containing transmembrane-1 (LETM1) is an important mitochondrial protein, while its function in endometrial cancer remains unknown. This study aimed to explore the function of LETM1 in endometrial cancer and reveal the underlying mechanisms involving carboxy-terminal modulator protein (CTMP). Immunohistochemistry was performed to detect the expression of LETM1 and CTMP in normal, atypical hyperplastic and endometrial cancer endometrial tissues. LETM1 and CTMP were silenced in two endometrial cancer cell lines (ISK and KLE), which were verified by western blot. Cell viability, colony number, migration and invasion were detected by cell counting kit-8, colony formation, wound healing and trans-well assays, respectively. A xenograft mouse model was established to determine the antitumor potential of LETM1/CTMP silencing in vivo. In addition, CTMP was overexpressed to evaluate its regulatory relationship with LETM1 in endometrial cancer cells. The expression of LETM1 and CTMP proteins were higher in endometrial cancer tissues than atypical hyperplastic tissues and were higher in atypical hyperplastic tissues than normal tissues. LETM1 and CTMP were also upregulated in ISK and KLE cells. Silencing of LETM1 or CTMP could decrease the viability, colony number, migration and invasion of endometrial cancer cells and the weight and volume of tumor xenografts. In addition, CTMP was downregulated by LETM1 silencing in KLE cells, and its overexpression enhanced the malignant characteristics of si-LETM1-transfected KLE cells. Silencing of LETM1 inhibits the malignant progression of endometrial cancer through downregulating CTMP.

Independent organelle and organelle—organelle interactions: essential mechanisms for malignant gynecological cancer cell survival

“…Expression of mitochondria-related molecules and OXPHOS affect endometrial cancer cell migration, invasion, disease severity, and prognosis ( 72 – 75 ); regulation of mitochondria is thus a primary way to induce apoptosis in endometrial cancer treatment ( 76 – 80 ). Expressions of many lysosomal and ER biogenic genes and factors affect endometrial cancer prognosis, effectively predict immune associations, and can be used as biomarkers ( 81 , 82 , 84 , 85 , 87 ).…”

“…Expression of mitochondrial endometrial protein leucine zipper/EF hand-containing transmembrane-1 (LETM1) is higher in endometrial carcinoma tissues compared with atypical hyperplasia tissues, and higher in atypical hyperplasia tissues compared with normal tissues. Moreover, silencing LETM1 downregulates carboxy-terminal modulator protein (CTMP), reducing the activity, migration, and invasion, and inhibiting the malignant progression, of endometrial cancer ( 72 ). MCU upregulation enhances mitochondrial activity and promotes clone formation and migration of endometrial cancer cells; it also interacts with VDAC1 to enhance regulation of mitochondrial calcium uptake and promote endometrial cancer progression ( 73 ).…”

Simvastatin restores pulmonary endothelial function in the setting of pulmonary over-circulation

“…Statins have also been shown to lower ADMA levels in the serum of patients [ 55 ] and may be rescuing CTMP, and also directly modulating Akt1 nitration, by impacting circulating and cellular production of ADMA. We have previously identified CTMP as a potential therapeutic target in pulmonary vascular disease, and it has similarly garnered interest in malignancies characterized by dysregulated Akt1 signaling [ 56 , 57 ]. In this study we associate CTMP levels with eNOS enzymatic performance both in vitro and in vivo , and also identify statins as a potential pharmacologic modulator of this regulatory mechanism.…”