<p>Downregulated MCOLN1 Attenuates The Progression Of Non-Small-Cell Lung Cancer By Inhibiting Lysosome-Autophagy</p>

Abstract

ObjectivesAutophagy plays various roles in non-small-cell lung cancer (NSCLC). MCOLN1, a reactive oxygen species sensor, can regulate autophagy via lysosomal Ca(2+); however, the role of MCOLN1 in NSCLC is largely unknown. This study aimed to explore the effects of MCOLN1 on proliferation, invasion and migration in NSCLC and the underling mechanisms.Materials and methodsThe tissues of NSCLC patients were collected, then MCOLN1 expression in tumor and adjacent tissues was measured and its relationship with pathological staging was analyzed. The Cell Counting Kit-8 (CCK-8) assay, wound healing assay and transwell migration assay were used to evaluate the proliferation, migration and invasion ability, respectively. Live-cell imaging and transmission electron microscopy (TEM) were used to observe autophagic flux and autolysosomes.ResultsIt was found that MCOLN1 expression was significantly decreased in human NSCLC tissues compared with normal lung tissues while more MCOLN1 in stage III–IV was shown than stage I–II, indicating that MCOLN1 increased along with the progression of NSCLC. Furthermore, CCK-8 assay, wound healing assay and transwell migration assay confirmed that the inhibition of MCOLN1 suppressed NSCLC cells proliferation migration and invasion. Overexpression of MCOLN1 promoted autophagy in A549 and H1299 cells with increased LC3-II/I, lamp1 expression and autolysosomes as well as autophagic flux shown by live-cell imaging and TEM.ConclusionOur study shows that downregulated MCOLN1 reduced lysosome-autophagy activity contributing to inhibited tumor progression, which reveals a novel role of MCOLN1 in NSCLC, and targeting MCOLN1 may be a therapeutic potential for NSCLC.

Suppression of autophagy facilitates hydrogen gas‑mediated lung cancer cell apoptosis

“…In lung cancer, inhibition of autophagy enhances the anti-angiogenic property of anlotinib (32), suggesting an angiogenic role of autophagy in lung cancer. Yin et al (33) reported that inhibition of autophagy induced by mucolipin-1 (which is a member of the transient receptor potential cation channel family) downregulation repressed the progression of lung cancer. Li et al (34), demonstrated that autophagy enhancement caused by apurinic endonuclease 1 Figure 4.…”

Endolysosomal TRPMLs in Cancer

“…The link between TRPMLs expression and the clinical characteristics of patients with cancer has also been reported. Yin et al [ 122 ] found that the expression of TRPML1 increases along with the progression of human nonsmall-cell lung cancer (NSCLC). Similarly, by evaluating the expression levels of TRPML1 in tumor tissues from 82 pancreatic ductal adenocarcinoma (PDAC) patients, Hu et al found that a higher TRPML1 expression level is associated with the poor clinical characteristics of these PDAC patients [ 123 ].…”

“…TRPML1 has been suggested to promote autophagy by facilitating multiple steps of autophagy, including autophagy induction [ 131 ], autophagosome-lysosome fusion [ 1 , 132 ], autolysosome degradation [ 133 , 134 , 135 ], and autophagic lysosome reformation (ALR) [ 27 , 133 ]. Inhibition of TRPML1 decreases autophagy activity and reduces proliferation, migration and invasion of NSCLC cells [ 122 ]. Recent studies have demonstrated that TRPML3 also plays an important role in regulating autophagy [ 53 , 54 , 55 ].…”

Deciphering the Role of Ca2+ Signalling in Cancer Metastasis: From the Bench to the Bedside

“…Additionally, this study identified for the first time the mechanism of action of tetrabromobisphenol A (TBBPA), a toxin that has been linked to hepatic cancer invasion and migration, finding that TBBPA evoked endolysosomal Ca 2+ signals upon binding to TRPML1 [ 34 ]. An increased expression of transient receptor potential mucolipin1 (TRPML1) was also detected in advanced stages (III–IV) compared to early stages (I–II) of tumourigenesis in patients with non-small-cell lung cancer (NSCLC); TRPML1 silencing or inhibition in vitro impaired pathophysiological processes related to metastatic NSCLC cancer, indicating that enhanced expression of mucolipin 1 was involved in cancer progression and metastasis by promoting cell invasion, proliferation and migration in NSCLC [ 35 ]. TRPML-2 mRNA and protein levels were found to be elevated in brain cancer patients and correlated with advanced pathological grades (from astrocytoma (I) to glioblastoma (IV)) [ 36 ].…”