Lung cancer is a main cause of death all over the world with a high incidence rate. Metastasis into neighboring and distant tissues as well as resistance of cancer cells to chemotherapy demand novel strategies in lung cancer therapy. Curcumin is a naturally occurring nutraceutical compound derived from Curcuma longa (turmeric) that has great pharmacological effects, such as anti-inflammatory, neuroprotective, and antidiabetic. The excellent antitumor activity of curcumin has led to its extensive application in the treatment of various cancers. In the present review, we describe the antitumor activity of curcumin against lung cancer. Curcumin affects different molecular pathways such as vascular endothelial growth factors, nuclear factor-κB (NF-κB), mammalian target of rapamycin, PI3/Akt, microRNAs, and long noncoding RNAs in treatment of lung cancer. Curcumin also can induce autophagy, apoptosis, and cell cycle arrest to reduce the viability and proliferation of lung cancer cells. Notably, curcumin supplementation sensitizes cancer cells to chemotherapy and enhances chemotherapy-mediated apoptosis. Curcumin can elevate the efficacy of radiotherapy in lung cancer therapy by targeting various signaling pathways, such as epidermal growth factor receptor and NF-κB. Curcumin-loaded nanocarriers enhance the bioavailability, cellular uptake, and antitumor activity of curcumin. The aforementioned effects are comprehensively discussed in the current review to further direct studies for applying curcumin in lung cancer therapy.

Versatile role of curcumin and its derivatives in lung cancer therapy

Abstract Background Chemoresistance to cisplatin (DDP) remains a major challenge in advanced gastric cancer (GC) treatment. Although accumulating evidence suggests an association between dysregulation of long non‐coding RNAs (lncRNAs) and chemoresistance, the regulatory functions and complexities of lncRNAs in modulating DDP‐based chemotherapy in GC remain under‐investigated. This study was designed to explore the critical chemoresistance‐related lncRNAs in GC and identify novel therapeutic targets for patients with chemoresistant GC. Methods Chemoresistance‐related lncRNAs were identified through microarray and verified through a quantitative real‐time polymerase chain reaction (qRT‐PCR). Proteins bound by lncRNAs were identified through a human proteome array and validated through RNA immunoprecipitation (RIP) and RNA pull‐down assays. Co‐immunoprecipitation and ubiquitination assays were performed to explore the molecular mechanisms of the Musashi2 (MSI2) post‐modification. The effects of LINC00942 (LNC942) and MSI2 on DDP‐based chemotherapy were investigated through MTS, apoptosis assays and xenograft tumour formation in vivo. Results LNC942 was found to be up‐regulated in chemoresistant GC cells, and its high expression was positively correlated with the poor prognosis of patients with GC. Functional studies indicated that LNC942 confers chemoresistance to GC cells by impairing apoptosis and inducing stemness. Mechanically, LNC942 up‐regulated the MSI2 expression by preventing its interaction with SCFβ‐TRCP E3 ubiquitin ligase, eventually inhibiting ubiquitination. Then, LNC942 stabilized c‐Myc mRNA in an N6‐methyladenosine (m6A)‐dependent manner. As a potential m6A recognition protein, MSI2 stabilized c‐Myc mRNA with m6A modifications. Moreover, inhibition of the LNC942‐MSI2‐c‐Myc axis was found to restore chemosensitivity both in vitro and in vivo. Conclusions These results uncover a chemoresistant accelerating function of LNC942 in GC, and disrupting the LNC942‐MSI2‐c‐Myc axis could be a novel therapeutic strategy for GC patients undergoing chemoresistance.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ctm2.703

LncRNA LINC00942 promotes chemoresistance in gastric cancer by suppressing MSI2 degradation to enhance c‐Myc mRNA stability

Deregulation of protein post-translational modifications is intensively involved in the etiology of diseases, including degenerative diseases, inflammatory injuries, and cancers. Acetylation is one of the most common post-translational modifications of proteins, and the acetylation levels are controlled by two mutually antagonistic enzyme families, histone acetyl transferases (HATs) and histone deacetylases (HDACs). HATs loosen the chromatin structure by neutralizing the positive charge of lysine residues of histones; whereas HDACs deacetylate certain histones, thus inhibiting gene transcription. Compared with HATs, HDACs have been more intensively studied, particularly regarding their clinical significance. HDACs extensively participate in the regulation of proliferation, migration, angiogenesis, immune escape, and therapeutic resistance of cancer cells, thus emerging as critical targets for clinical cancer therapy. Compared to HATs, inhibitors of HDAC have been clinically used for cancer treatment. Here, we enumerate and integratethe mechanisms of HDAC family members in tumorigenesis and cancer progression, and address the new and exciting therapeutic implications of single or combined HDAC inhibitor (HDACi) treatment. 

The emerging roles of HDACs and their therapeutic implications in cancer.

FGF21 promotes non-small cell lung cancer progression by SIRT1/PI3K/AKT signaling.

Chemoresistance is one of the most important challenges in the clinical management of lung cancer. SIRT1 is a NAD dependent protein deacetylase and implicated in diverse cellular processes such as DNA damage repair, and cancer progression. SIRT1 is upregulated in chemoresistant lung cancer cells, genetic knockdown or chemical inhibition of SIRT1 reversed chemoresistance by enhancing DNA damage and apoptosis activation, accompanied with XRCC1 degradation. E3 ligase β-TrCP catalyzed the poly-ubiquitination of XRCC1 to promote its proteasome-dependent degradation. SIRT1 bound and deacetylated XRCC1 at lysine K260, K298 and K431, preventing it from β-TrCP-dependent ubiquitination. Mutations of these three lysine sites in XRCC1 abrogated the interaction with β-TrCP and prolonged the half-life of XRCC1 protein. Here, we describes SIRT1 confers chemoresistance to lung cancer cells by deacetylating and stabilizing XRCC1. Therefore, targeting SIRT1 might be a new strategy to manage the chemoresistance of lung cancer, and probably other cancers.

/pdf/sirt1-deacetylated-and-stabilized-xrcc1-to-promote-1hvjt4gw27.pdf

SIRT1 deacetylated and stabilized XRCC1 to promote chemoresistance in lung cancer


 Background Hypoxia is an important characteristic of the tumor microenvironment. Tumor cells can survive and propagate under the hypoxia stress through activating a series of adaption response. The study on the mechanism of tumor hypoxia adaption is still of urgent significance to find effective therapeutic targets and strategies. Methods We compared the protein expression of KDM5B in tumor or normal tissues and cell lines by IHC and Western blotting (WB). CCK8 and cell colony formation assay was performed to evaluate the KDM5B caused growth inhibition. The transcriptome analysis, quantitative real-time PCR (qPCR), flow cytometry analysis, chromatin immunoprecipitation (ChIP) were for exploring the downstream mechanism. And the SUMOylation assay and Ni-beads pull-down assay and co-immunoprecipitation (co-IP) were used to illustrate how did post-translation modification (PTM) regulate the KDM5B protein stabilization. Finally, tumor xenograft assay in nude mice verified the findings in vivo. Results We found that lysine-specific demethylase 5B (KDM5B) was upregulated in gastric cancer (GC) under hypoxia condition. The genetic knockdown or chemical inhibition of KDM5B impaired the growth of GC cell adapted to hypoxia. Inhibition of KDM5B caused significant cell cycle G1/S arrest through the transcription upregulation of cyclin-dependent kinase inhibitor 1 (CDKN1, also known as p21). Interestingly, the upregulation of KDM5B in hypoxia response was associated with the SUMOylation of KDM5B. SUMOylation stabilized KDM5B protein by reducing the competitive modification of ubiquitination. Furthermore, protein inhibitor of activated STAT 4 (PIAS4) was determined as the SUMO E3 ligase which increased the interaction with KDM5B under hypoxia condition. As the result, co-targeting KDM5B significantly improved the anti-tumor efficacy of antiangiogenic therapy in vivo. Conclusion Taken together, PIAS4 mediated SUMOylation stabilized KDM5B protein through disturbing ubiquitination-dependent proteasomal degradation to overcome hypoxia adaption. Targeting SUMOylation-dependent KDM5B upregulation might be considered when antiangiogenic therapy was applied in cancer treatment.

/pdf/hypoxia-stimulates-sumoylation-dependent-stabilization-of-2hduvxi3e7.pdf

Hypoxia stimulates SUMOylation-dependent stabilization of KDM5B

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SIRT1 deacetylated and stabilized XRCC1 to promote chemoresistance in lung cancer

Hypoxia stimulates SUMOylation-dependent stabilization of KDM5B