TOMM20 as a potential therapeutic target of colorectal cancer

Abstract

Translocase of outer mitochondrial membrane 20 (TOMM20) plays an essential role as a receptor for proteins targeted to mitochondria. TOMM20 was shown to be overexpressed in various cancers. However, the oncological function and therapeutic potential for TOMM20 in cancer remains largely unexplored. The purpose of this study was to elucidate the underlying molecular mechanism of TOMM20’s contribution to tumorigenesis and to explore the possibility of its therapeutic potential using colorectal cancer as a model. The results show that TOMM20 overexpression resulted in an increase in cell proliferation, migration, and invasion of colorectal cancer (CRC) cells, while siRNA-mediated inhibition of TOMM20 resulted in significant decreases in cell proliferation, migration, and invasion. TOMM20 expression directly impacted the mitochondrial function including ATP production and maintenance of membrane potential, which contributed to tumorigenic cellular activities including regulation of S phase cell cycle and apoptosis. TOMM20 was overexpressed in CRC compared to the normal tissues and increased expression of TOMM20 to be associated with malignant characteristics including a higher number of lymph nodes and perineural invasion in CRC. Notably, knockdown of TOMM20 in the xenograft mouse model resulted in a significant reduction of tumor growth. This is the first report demonstrating a relationship between TOMM20 and tumorigenesis in colorectal cancer and providing promising evidence for the potential for TOMM20 to serve as a new therapeutic target of colorectal cancer.

Translocase of the outer mitochondrial membrane complex subunit 20 (TOMM20) facilitates cancer aggressiveness and therapeutic resistance in chondrosarcoma

“…We found that TOMM20 is expressed in human chondrosarcomas and when overexpressed in chondrosarcoma cells, increases expression of markers of cancer aggressiveness and promotes tumor growth. These data suggest that TOMM20 expression promotes tumor growth by promoting mitochondrial metabolism, increasing proliferation, and inducing markers of an epithelial to mesenchymal transition (EMT), which are consistent with other studies showing an association between TOMM20 expression and outcomes in human cancers [26] [27] [28] [29] [30]. These changes in Journal Pre-proof chondrosarcoma cells induced by TOMM20 overexpression also induce resistance to cell cycle specific chemotherapy agents.…”

“…We studied the expression of the translocase of the outer mitochondrial membrane subunit 20 (TOMM20) in human chondrosarcomas. High TOMM20 expression has been described in human epithelial and lymphoid cancers and is associated with poor outcomes [26] [30]. We describe for the first time that TOMM20 is highly expressed in high grade compared to low grade human chondrosarcomas, suggesting that aggressive chondrosarcomas have increased mitochondrial metabolism.…”

“…Therefore, cells with greater mitochondrial mass and higher mitochondrial activity have more TOMM20 expression [23]. TOMM20 has previously been shown to be highly expressed in human epithelial and lymphoid cancers and is a prognostic biomarker [26] [27] [28] [29] [30].…”

Ginsenoside Rh2 inhibits HeLa cell energy metabolism and induces apoptosis by upregulating voltage‑dependent anion channel 1

“…The mechanism by which 20(S)-GRh2 regulates cell death and energy metabolism was next elucidated. 20(S)-GRh2 influenced the protein levels of VDAC1 and HK2, which are important regulators of glucose metabolism (45,46), and the changes in VdAc1 and HK2 protein levels were inversely associated. Treatment with 20(S)-GRh2 inhibited mitochondrial metabolism, leading to dissociation of HK2 from mitochondrial VdAc1, which regulated the transfer of Bax to the mitochondria and allowed cytochrome c to enter the cytosol via the outer mitochondrial membrane.…”

Ethionine Suppresses Mitochondria Autophagy and Induces Apoptosis via Activation of Reactive Oxygen Species in Neural Tube Defects

“…Studies have shown that as MMP decreases, mitochondrialspecific protease presenilin-associated diamond-shaped protein (PARL) and mitochondrial processing peptidase (MPP) are inactivated, and thus resulted in regulation of PINK1 levels (15). Recent studies have reported that TOMM20 plays an essential role as a receptor for proteins which can target mitochondria (16). However, the mechanism of maternal methionine cycle disorders that represses autophagy during neural tube development is still not clear.…”