A novel role of transient receptor potential mucolipin1 (TRPML1) in protecting against imidazole-induced cytotoxicity

Abstract

Lysosomotropic amines cause serious side effects such as cytoplasmic vacuolation and cell death. TRPML1 (also known as mucolipin1), a member of the transient receptor potential (TRP) protein family, may regulate fusion/fission of vesicles along the endocytic pathway and some aspects of lysosomal ion homeostasis. Nevertheless, it is still unknown whether TRPML1 is involved in death of mammalian cells induced by lysosomotropic agents. In this study, imidazole was used as a model to investigate the role of TRPML1 in the cytotoxicity of lysosomotropic agents. Overexpression of wild-type TRPML1 inhibited imidazole-induced vacuole formation and cell death in human endometrial adenocarcinoma (HEC-1B) cells. In contrast, siRNA-mediated TRPML1 knockdown increased the cell death induced by imidazole. Bafilomycin A1 raises the pH of acidic organelles and therefore suppresses accumulation of weak bases in them. Similarly, lysosomal pH was raised in TRPML1-overexpressing cells; therefore, we inferred that TRPML1 protected against imidazole toxicity by regulating the pH of acidic organelles. We concluded that TRPML1 had a novel role in protecting against lysosomotropic amine toxicity.

Transient Receptor Potential Mucolipin-1 Channels in Glioblastoma: Role in Patient’s Survival

“…TRPML-1 plays a role in the control of cell viability and in chaperone-mediated autophagy [16]. It is involved in death of mammalian cells induced by lysosomotropic agents [26]. TRPML-1 is considered a reactive oxygen species (ROS) sensor localized on the lysosomal membrane that orchestrates an autophagy-dependent negative-feedback program to mitigate oxidative cell stress [27].…”

MCOLN1 Promotes Proliferation and Predicts Poor Survival of Patients with Pancreatic Ductal Adenocarcinoma

“…Our research was the precedent experiment which systematically studied the role of STK32C in promoting the proliferation in PDAC. Liu et al's study found that overexpression of MCOLN1 inhibited imidazole-induced vacuole formation and cell death in human endometrial adenocarcinoma (HEC-1B) cells [16]. In contrast, knockdown MCOLN1 increased the cell death induced by imidazole [16].…”

“…Liu et al's study found that overexpression of MCOLN1 inhibited imidazole-induced vacuole formation and cell death in human endometrial adenocarcinoma (HEC-1B) cells [16]. In contrast, knockdown MCOLN1 increased the cell death induced by imidazole [16]. Moreover, a report in 2019 demonstrated that MCOLN1 inhibition could attenuate HRAS nanoclustering and plasma membrane abundance, ERK phosphorylation, and cell proliferation [33].…”

“…Besides, MCOLN1 was reported to protect against imidazole-induced cytotoxicity. Also, inhibition of MCOLN1 resulted in severe combined immunodeficiency diseases [16, 17]. However, the potential role of MCOLN1 in human carcinoma development has not been studied clearly.…”

Emerging Role of Mucolipins TRPML Channels in Cancer

“…In human endometrial adenocarcinoma (HEC-1B) cells, TRPML1 overexpression inhibits vacuole formation and cell death induced by the lysosomotropic agent imidazole. In contrast, TRPML1 knockdown increases cell death induced by the same treatment (10). Thus, it was supposed that TRPML1 is able to protect against this kind of drug by regulating the pH of acidic organelles.…”