HRAS‐driven cancer cells are vulnerable to TRPML1 inhibition

Jung, Jewon; Cho, Kwang Jin; Naji, Ali; Clemons, Kristen; Wong, Ching On; Villanueva, Mariana; Gregory, Steven R.; Karagas, Nicholas E.; Tan, Lingxiao; Luan, Hong; Rousseau, Morgan A; Tomasevich, Kelly M.; Sikora, Andrew G.; Levental, Ilya; Hoeven, Dharini van der; Zhou, Yong; Hancock, John F.; Venkatachalam, Kartik

doi:10.15252/embr.201846685

Cited by 64 publications

(80 citation statements)

References 78 publications

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“…Moreover, recently, it has been reported that the endolysosomal TRPML1 channel, belonging to the mucolipin TRP channel family, is required for cancer cell proliferation bearing HRAS mutations and that TRPML1 expression was significantly elevated in HRAS-positive tumors and inversely correlated with poor prognosis. Mutations of KRAS and HRAS in cancer affect the efficacy of chemotherapy; changes in TRP channel expression could overcome drug resistance and increase the sensitivity of cancer cells to chemotherapy [110]. The mucolipin TRPML1 receptor is also required in ME cells to negatively regulate MAPK and mTORC1 signaling [111] and in TNBC, where it regulates cancer development by promoting mTORC1 and purinergic signaling pathways [112].…”

Section: Discussionmentioning

confidence: 99%

Transient Receptor Potential Cation Channels in Cancer Therapy

et al. 2019

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In mammals, the transient receptor potential (TRP) channels family consists of six different families, namely TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPML (mucolipin), TRPP (polycystin), and TRPA (ankyrin), that are strictly connected with cancer cell proliferation, differentiation, cell death, angiogenesis, migration, and invasion. Changes in TRP channels’ expression and function have been found to regulate cell proliferation and resistance or sensitivity of cancer cells to apoptotic-induced cell death, resulting in cancer-promoting effects or resistance to chemotherapy treatments. This review summarizes the data reported so far on the effect of targeting TRP channels in different types of cancer by using multiple TRP-specific agonists, antagonists alone, or in combination with classic chemotherapeutic agents, microRNA specifically targeting the TRP channels, and so forth, and the in vitro and in vivo feasibility evaluated in experimental models and in cancer patients. Considerable efforts have been made to fight cancer cells, and therapies targeting TRP channels seem to be the most promising strategy. However, more in-depth investigations are required to completely understand the role of TRP channels in cancer in order to design new, more specific, and valuable pharmacological tools.

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Section: Discussionmentioning

confidence: 99%

Transient Receptor Potential Cation Channels in Cancer Therapy

et al. 2019

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“…Besides LSDs, emerging evidence suggests that TRPML1 is also important for cancer cell survival [59][60][61]. Interestingly, the effect of TRPML1 activity modulation on cancer cell survival differs, possibly dependent on the type of cancers and stimuli.…”

Section: Redox-sensing Lysosomal Ion Channels and Diseasesmentioning

confidence: 99%

Ion channels as potential redox sensors in lysosomes

2019

Channels

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Lysosomes are central organelles that recycle materials and energy to maintain intracellular homeostasis. Lysosomes are capable of sensing environmental cues such as nutrition to regulate their function accordingly. Whether lysosomes can sense redox signaling, however, was unclear. Here in this review, we summarized recent evidence of lysosomal ion channel as redox sensors for this organelle. We also discussed their roles in lysosomal diseases that features imbalanced redox.

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“…Disruption of lysosomal acidification diminishes mitochondrial respiration (28) and knockdown of the lysosomal V-ATPase attenuates mitochondrial bioenergetics, induces mitochondrial fission, and increased reactive oxygen species (ROS) production to promote hepatoma cancer cell death (29). Recently, we (30) and others (31,32), demonstrated the role of Transient Receptor Potential Mucolipin 1 (TRPML1 or ML1), a lysosomal Ca 2+ -release channel, in driving breast cancer survival and proliferation. Specifically, we showed that loss of TRPML1 hampers triple-negative breast cancer (TNBC) growth and invasion by modulating mTORC1 activity and lysosomal ATP release to the extracellular space.…”

Section: Introductionmentioning

confidence: 99%

The lysosomal TRPML1 channel promotes breast cancer survival by supporting mitochondrial function and cellular metabolism

Almasi

Kennedy

Yoast

et al. 2020

Preprint

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Triple-negative breast cancer (TNBC) is an aggressive subtype representing approximately 10%-20% of breast cancers and lacking effective therapies. TRPML1, which is a lysosomal Ca2+ release channel upregulated in TNBC, promotes TNBC tumor growth. Here we show a novel crosstalk between lysosomes and mitochondria mediated by TRPML1 in TNBC. TRPML1 is required for the maintenance of mitochondrial function and reactive oxygen species (ROS) homeostasis. TRPML1 knockdown inhibits TNBC mitochondrial respiration, glycolysis and ATP production, leading to reduced proliferation, promotion of cell cycle arrest and apoptosis with enhanced global and mitochondrial ROS. Further, TRPML1 downregulation enhances the cytotoxic effect of Doxorubicin in TNBC cells. Our data reveal a hitherto unknown link between lysosomal TRPML1 channels and mitochondrial metabolism and suggest that TRPML1 inhibition in combination with established chemotherapies could be an effective strategy against TNBC tumors.

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HRAS‐driven cancer cells are vulnerable to TRPML1 inhibition

Cited by 64 publications

References 78 publications

Transient Receptor Potential Cation Channels in Cancer Therapy

Transient Receptor Potential Cation Channels in Cancer Therapy

Ion channels as potential redox sensors in lysosomes

The lysosomal TRPML1 channel promotes breast cancer survival by supporting mitochondrial function and cellular metabolism

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