Targeting the Lysosome for Cancer Therapy

Towers, Christina G.; Thorburn, Andrew

doi:10.1158/2159-8290.cd-17-0996

Cited by 59 publications

(44 citation statements)

References 12 publications

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“…In our study, the disruption of lysosomal activity induced by TBM was due to the dysfunction of lysosomal enzyme. In addition, a stale lysosomal function is essential for complete autophagy and cellular homeostasis, especially in tumor cells suffering from stress condition, in contrast, accumulation of autophagolysosomes due to defect lysosomal activity will result cancer cells death 56 , 57 . It is therefore conceivable that the late stage inhibition of autophagy is contributed to the cytotoxicity of TBM in cervical cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Tubeimoside I induces accumulation of impaired autophagolysosome against cervical cancer cells by both initiating autophagy and inhibiting lysosomal function

Feng

Zhou

et al. 2018

Cell Death Dis

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Cervical cancer is one of the most aggressive human cancers with poor prognosis due to constant chemoresistance and repeated relapse. Tubeimoside I (TBM) has been identified as a potent antitumor agent that inhibits cancer cell proliferation by triggering apoptosis and inducing cell cycle arrest. Nevertheless, the detailed mechanism remains unclear and needs to be further elucidated, especially in cervical cancer. In this study, we found that TBM could induce proliferation inhibition and cell death in cervical cancer cells both in vitro and in vivo. Further results demonstrated that treatment with TBM could induce autophagosome accumulation, which was important to TBM against cervical cancer cells. Mechanism studies showed that TBM increased autophagosome by two pathways: First, TBM could initiate autophagy by activating AMPK that would lead to stabilization of the Beclin1-Vps34 complex via dissociating Bcl-2 from Beclin1; Second, TBM could impair lysosomal cathepsin activity and block autophagic flux, leading to accumulation of impaired autophagolysosomes. In line with this, inhibition of autophagy initiation attenuated TBM-induced cell death, whereas autophagic flux inhibition could exacerbated the cytotoxic activity of TBM in cervical cancer cells. Strikingly, as a novel lethal impaired autophagolysosome inducer, TBM might enhance the therapeutic effects of chemotherapeutic drugs towards cervical cancer, such as cisplatin and paclitaxel. Together, our study provides new insights into the molecular mechanisms of TBM in the antitumor therapy, and establishes potential applications of TBM for cervical cancer treatment in clinic.

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Section: Discussionmentioning

confidence: 99%

Tubeimoside I induces accumulation of impaired autophagolysosome against cervical cancer cells by both initiating autophagy and inhibiting lysosomal function

Feng

Zhou

et al. 2018

Cell Death Dis

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“…Lysosomes mediate MDR in many cancers, such as those showing resistance to cisplatin, sorafenib, doxorubicin, and oxaliplatin [30]. Lysosomes recycle organelles and proteins in cells [50] and they play extensive roles in various diseases, including cancers, making them an attractive and targetable node for therapeutic intervention. In liver cancer, lysosomes are known to be involved in the chemoresistance of HCC cells [51,52].…”

Section: Discussionmentioning

confidence: 99%

Dysregulated FAM215A Stimulates LAMP2 Expression to Confer Drug-Resistant and Malignant in Human Liver Cancer

Huang

Lin

Cheng

et al. 2020

Cells

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Hepatocellular carcinoma (HCC) is one of the most common and aggressive human malignancies worldwide. Long non-coding (lnc) RNAs regulate complex cellular functions, such as cell growth, differentiation, metabolism, and metastasis. Although deregulation of lncRNA expression has been detected in HCC, many of the hepato-carcinogenesis-associated lncRNAs remain yet unidentified. Here, we aimed to investigate the involvement of a specific HCC-dysregulated lncRNA, FAM215A, and characterize its molecular regulation mechanism. We show for the first time that FAM215A is overexpressed in HCC, and its expression level correlates with tumor size, vascular invasion, and pathology stage. Overexpression of FAM215A accelerates cell proliferation and metastasis in HCC cells. According to Gene Expression Omnibus Dataset analysis, FAM215A is induced in doxorubicin (DOX)-resistant HCC cells. Overexpression of FAM215A increases DOX resistance in two HCC cell lines, and this is associated with enhanced expression of lysosome-associated membrane protein 2 (LAMP2). FAM215A interacts with LAMP2 to protect it from ubiquitination. Together, our results show that the lncRNA, FAM215A, is highly expressed in HCC, where it interacts with and stabilizes LAMP2 to increase tumor progression while decreasing doxorubicin sensitivity.

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“…While the nature of the observed aggregates is to be investigated, protein aggregation is recognized as hallmark of cancer linked to endoplasmic reticulum (ER) stress [72,73]. It may also represent malfunctioned lysosomes also linked to cancer and ER stress [74,75]. Aberrant activation of signaling proteins like mTORC1 a key IQGAP1 partner in insulin secretion and cell size, and E-cadherin, an IQGAP1 partner in cell adhesion, by lysosome targeting has been reported [76,77].…”

Section: Differential Localization Of Iqgap1 and Brca1 In Patients' Tmentioning

confidence: 99%

IQGAP1 control of centrosome function defines distinct variants of triple negative breast cancer

Osman

James

Yakirevich³

2020

Oncotarget

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Triple negative breast cancer (TNBC) is a heterogenous and lethal disease that lacks diagnostic markers and therapeutic targets; as such common targets are highly sought after. IQGAP1 is a signaling scaffold implicated in TNBC, but its mechanism is unknown. Here we show that IQGAP1 localizes to the centrosome, interacts with and influences the expression level and localization of key centrosome proteins like BRCA1 and thereby impacts centrosome number. Genetic mutant analyses suggest that phosphorylation cycling of IQGAP1 is important to its subcellular localization and centrosome-nuclear shuttling of BRCA1; dysfunction of this process defines two alternate mechanisms associated with cell proliferation. TNBC cell lines and patient tumor tissues differentially phenocopy these mechanisms supporting clinical existence of molecularly distinct variants of TNBC defined by IQGAP1 pathways. These variants are defined, at least in part, by differential mis-localization or stabilization of IQGAP1-BRCA1 and rewiring of a novel Erk1/2-MNK1-JNK-Akt-β-catenin signaling signature. We discuss a model in which IQGAP1 modulates centrosome-nuclear crosstalk to regulate cell division and imparts on cancer. These findings have implications on cancer racial disparities and can provide molecular tools for classification of TNBC, presenting IQGAP1 as a common target amenable to personalized medicine.

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Targeting the Lysosome for Cancer Therapy

Cited by 59 publications

References 12 publications

Tubeimoside I induces accumulation of impaired autophagolysosome against cervical cancer cells by both initiating autophagy and inhibiting lysosomal function

Tubeimoside I induces accumulation of impaired autophagolysosome against cervical cancer cells by both initiating autophagy and inhibiting lysosomal function

Dysregulated FAM215A Stimulates LAMP2 Expression to Confer Drug-Resistant and Malignant in Human Liver Cancer

IQGAP1 control of centrosome function defines distinct variants of triple negative breast cancer

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