Moxidectin induces lethal autophagy arrest via CFTR

doi:10.21203/rs.3.rs-1731984/v1

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Moxidectin induces lethal autophagy arrest via CFTR

https://doi.org/10.21203/rs.3.rs-1731984/v1

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Colorectal cancer (CRC) is a cancer with a high morbidity and mortality worldwide. Hence， developing new therapeutic drugs for CRC is very important. Moxidectin (MOX) has shown good anti-glioblastoma effect both in vitro and in vivo, This study aimed to elucidate the anti-CRC effect of MOX and its potential mechanism. By investigating the influence of MOX on the viability, apoptosis, necrosis and autophagy of colorectal cancer cells (HCT15 and SW620) and its underlying mechanisms. It was found that MOX can induce autophagy arrest, promote autophagy initiation, inhibit autophagic flux and cell proliferation, simultaneously PI3K-Akt-mTOR signaling pathway and microtubule acetylation. Furthermore, MOX suppressed the growth of xenograft tumors, which was consistent with the in vitro results.

moxidectin

colorectal cancer

autophagosome

accumulation

CFTR

CRC is a common malignancy ^[1]. At present, surgery and chemotherapy are nevertheless remain the methods for CRC treatment, but the disadvantages of serious toxic side effects and easy development of drug resistance have limited efficacy ^[2]. Therefore, it is imperative to find new therapeutic drugs for CRC. The development of new targeted drugs is a long process with high cost and low success rate ^[3]. Therefore, marketed drugs and developing their new indications has become a new direction to accelerate the development of anti-tumor drugs, which is of great significance to the optimization of cancer treatment plans.

In recent years, studies have found that azithromycin, avermectin, clarithromycin, ivermectin and other macrolide antibiotics (ML) have excellent anticancer activity ^{[4, 5]}. There have been confirmed the potential role of azithromycin in the treatment of CRC ^[6]. Ivermectin inhibits cell proliferation by promoting ROS-mediated mitochondrial apoptosis pathway and inducing S-phase arrest in CRC cells, while inhibiting breast cancer cell growth and inducing glioblastoma cell death in vitro and in vivo ^{[7, 8]}. MOX is a semi-synthetic single-ingredient macrolide antibiotic produced by fermentation of streptomycessp, with a chemical structure very similar to ivermectin, which has been formulated into oral tablets for the treatment of onchocerciasis patients aged 12 years and older ^{[9, 10, 11]}. Research shows that MOX can effectively curb the proliferation of glioblastoma through autophagy and apoptosis pathways ^[12], suggesting that it may also have a good antitumor effect on CRC.

Autophagy is a highly conserved degradation process in which ATG proteins form double-membrane vesicles called autophagosomes around organelles, proteins, and intracellular pathogens by activating the AMPK signaling pathway or inhibiting the mTOR signaling pathway. After fusing with lysosomes, by degrading the internal components of autophagosomes and recycling metabolites to promote cell survival ^[13]. Concurrently, excessive autophagy or reduced levels could interfere with cell proliferation, survival, differentiation, etc ^[14]. Due to the dual role of autophagy, targeting autophagy is also a promising therapeutic strategy for CRC ^[15]. Consequently, it is of great significance to clarify whether MOX is involved in the treatment of CRC through autophagy, and provide a new therapeutic strategies.

In this study, researchers clarified the anticancer effect of MOX on CRC, revealed the impact of autophagy arrest on cancer therapy, and demonstrated the potential efficacy of MOX on CRC.

MOX inhibits colorectal cancer cell growth

To study the effect of MOX on the growth of colorectal cancer cells. Proliferation rates of various CRC cells after treatment at different concentrations were determined using MTT. As shown in Figure 1A, MOX had a slight effect on the growth of normal intestinal epithelial NCM460 cells, but had a significant inhibitory effect on HCT15 and SW620 cells, and the cell viability decreased in a dose-dependent manner. Simultaneous colony formation assayed the long-term effects of MOX on cells (Fig. 1B), consistent with the MTT results. Next, investigated the mechanism by which MOX inhibits the proliferation of CRC cells. Whereas it can induce autophagy and apoptosis in glioma cells, we used western blot to detect the level of cleaved-caspase3 and the result shown that no significant cells apoptosis of treatment, which was also confirmed by flow cytometry AnnexinV-PI. LDH (lactate dehydrogenase) release experiments found that MOX does not also cause cell necrosis. A series of results showed the way that moxidectin inhibited the proliferation of colorectal cancer cells in vitro was independent of cell necrosis and apoptosis.

Moxidectin induces autophagosome accumulation in CRC cells by promoting autophagy initiation and blocking autophagolysosomes

To further determine the inhibitory mechanism of MOX-induced CRC, we tried another cellular inhibitory mechanism, autophagy, and observed a marked increase in the accumulation of LC3 in CRC cells after MOX treatment (Fig.2A). Treated cells consistently exhibited significant accumulation of autophagic vesicles and LC3 punctate cells, as shown by transmission electron microscopy (Fig. 2B) and LC3 immunofluorescence staining (Fig. 2C). In addition to autophagy initiation, elevated levels of LC3 may also be the result of blocked autophagic flux and defective degradation capacity. We examined the levels of the autophagy-specific substrate SQSTM1/P62 and found that SQSTM1/P62 accumulated in both MOX-treated colorectal cancer cells (Fig. 2E), implying impaired of autophagic flux. To test this conjecture using tandem mRFP-GFP-tagged LC3 plasmids and as shown in Figure 2D, the number of LC3 puncta was significantly increased in MOX-treated cells, and a large percentage of puncta exhibited RFPGFP signal (autophagosome) rather than RFPGFP⁺⁺⁺⁻signal (autolysosomes), suggesting that an increase in autophagosome accumulation and a decrease in autolysosome formation. Taken together, these results suggest that MOX can drive autophagy initiation and block autophagosome-lysosome fusion to induce massive accumulation of autophagosomes, leading to autophagy arrest.

Moxidectin inhibits CRC cell growth by promoting autophagosome accumulation

To clarify the role of autophagy in MOX inhibition of CRC cell growth, As shown in the results of MTT (Fig. 3C) and clone formation (Fig. 3E) of CRC cells with 3-MA or CQ, it was found that 3-MA inhibited autophagy initiation (Fig. 3A), and rescued MOX-induced growth inhibition. In contrast, CQ treatment disrupted autophagosome-lysosome fusion in CRC cells and resulted in autophagosome accumulation (Fig. 3B), significantly aggravating MOX-induced growth inhibition, such as MTT (Fig. 3D) and colony formation (Fig. 3F). Interestingly, the addition of 3-MA did not significantly reduce the level of MOX-induced cellular SQSTM1/P62, suggesting that the accumulation of SQSTM1/P62 may not be related to autophagy alone. Overall, these results suggest that MOX inhibits CRC cell growth by promoting autophagy initiation and autophagosome accumulation.

MOX induces autophagy by inhibiting the AKT-mTOR pathway

Next, we investigated the underlying mechanism by which MOX induces autophagy. As the transcriptomic data showed, that MOX may induce mitochondrial dysfunction in CRC cells, which is closely related to autophagy. Then, we detected the mRNA level of the endoplasmic reticulum stress marker protein GRP78, which was significantly elevated after MOX treatment of CRC cells (Fig. 4A). The AKT-mTOR pathway is a master regulator of autophagy. Inhibition of the AKT-mTOR pathway induces autophagy under conditions such as nutrient deprivation or oxygen deprivation. We used immunoblotting to verify the activation status of this pathway. As shown in Figure 4B, p-AKT, p-mTOR and their downstream p-P70S6K were significantly decreased. To confirm that the pathway is involved in MOX-induced CRC cell growth inhibition, we used the AKT agonist SC-79 to restore MOX-induced AKT/mTOR inhibition. Activation of AKT significantly reduced the transformation of LC3II in MOX-treated cells (Fig. 4C), while increasing the growth of MOX-treated CRC cells (Fig. 4D, E). The series of results indicated that AKT/mTOR is an important medium of MOX-mediated autophagy and inhibitory for cell growth.

MOX triggers autophagy via CFTR

We found that the mRNA level of CFTR was significantly reduced after MOX treatment based on transcriptomic analysis, and RT-PCR validated this result (Fig. 5B, C). Furthermore, public databases indicated that CFTR was closely associated with colorectal cancer (Fig. 5A). It has recently been reported that CFTR misfolding or inhibition triggers endoplasmic reticulum stress-induced autophagy initiation, while mediating reduced levels of tubulin acetylation leading to impaired autophagosome-lysosome binding. This is consistent with our previous findings. We treated cells with 4-PB, a drug widely studied in CF model systems that boost trafficking of misfolded mutant CFTR to alleviate ER stress and promote microtubule acetylation, as shown in Figure.5D, reducing MOX-induced accumulation of SQSTM1/p62 and LC3. As well as rescue MOX-induced cell growth inhibition. Collectively, our findings suggest that MOX may inhibit cell growth through CFTR-mediated autophagy initiation and fusion of autophagosomes with lysosomes.

Inhibition of colorectal tumor growth by MOX in vivo

Our results suggest that blocking autophagic flux by MOX contributes to CRC growth inhibition in vitro, and we next established a xenograft tumor model to confirm the anticancer behavior of MOX in vivo. The results showed that MOX treatment for 15 days could significantly inhibit the growth of CRC (Fig. 6B, C, D) without significant body weight loss (Fig. 6A). It was shown that MOX has antitumor activity in vivo. Overall, we demonstrate that MOX may serve as a novel candidate for CRC therapy.

MOX is an FDA-approved antiparasitic oral tablet and is currently being explored as a potential anticancer agent in glioblastoma ^{[2,, 11, 16]}. In this study, we report that MOX also has potent anticancer effects on CRC. Interestingly, unlike its mechanism in GBM, MOX treatment for 36 h had no apparent apoptosis in CRC cells, which might be attributed to the anti-apoptotic phenotype ^{[17, 18]}. These findings suggest that MOX induced CRC suppression involves other growth inhibitory mechanisms.

In recent years, considerable attention has been paid to the role of autophagy in cancer therapy, which can improve anticancer therapy and play an integral role in tumor maintenance ^{[19, 20]}. In most cases, the treatment of cancer by autophagy is accompanied with an increased autophagic flux. However, our data show that MOX can promote autophagy initiation and block autophagosome-lysosome fusion leading to autophagy arrest and massive accumulation of autophagosomes. Inhibition of autophagosome formation reduces MOX-induced CRC suppression, whereas blocking autophagosome-lysosomal fusion increases the sensitivity of CRC cells to MOX. Multiple results confirm the critical role of autophagosome accumulation in MOX anti-CRC.

We further explored the signaling pathway of MOX-induced autophagy. The AKT/mTOR pathway is a common tumor therapy target and the maintenance of pathway homeostasis contributes to the occurrence of cancer^[21]. AKT signaling is involved in the regulation of cell proliferation, migration, invasion, and angiogenesis. AKT can phosphorylate and activate the downstream protein mTOR ^{[22, 23]}. We found that p-AKT, p-mTOR and p-p70S6K were decreased after MOX treatment in HCT15 and SW620 cells.It was further shown that MOX induced autophagy in HCT15 and SW620 cells through the AKT/mTOR signaling pathway.

In our current study, although AKT/mTOR axis involved in the initiation of autophagy induced by moxidectin has been demonstrated, our data show that moxidectin also leads to impaired autophagic flux. However, the specific reasons for the arrest of autophagy remain unknown. For the study, we used transcriptomics to screen a suspect protein CFTR, the only ABC protein that constitutes the pore-forming subunit of the ion channel ^[24]. Impaired CFTR function reduces the level of acetylation of microtubules and changes the transport capacity of microtubules, which is consistent with the study of impaired autophagic flux. At the same time, impaired CFTR function leads to ER stress, which in turn induces autophagy ^[25]. Then, we attempted to rescue MOX-induced cell growth inhibition using 4-PB, which can promote trafficking of misfolded mutant CFTR to alleviate ER stress and facilitate microtubule acetylation. However, we have yet to find direct evidence that MOX affects CFTR, and further research is needed to address this issue.

In conclusion, our study suggests that MOX is a potential drug against CRC, explaining the molecular mechanism of anticancer activity (Summary Fig. 7).It is Strongly suggested that moxidectin is a promising drug candidate of CRC.

Cell Lines and Cell Culture

Human colorectal cancer cell lines HCT15, SW620, DLD-1, HCT116, and NCM460 were purchased from Feiouer Biotechnology Co., Ltd. All cells were cultured in RPMI1640 supplemented with 10% fetal bovine serum (BI) in a 37°C incubator with 5% CO2.

Reagents and antibodies

Moxidectin, 3-methyladenine (3-MA), hydroxychloroquine (HCQ) purchased from selleck chemicals. Sodium 4-phenylbutyrate (4-PB) was purchased from Beijing Soleibo Technology Co, Ltd. Antibodies used in this study: LC3B (proteintech, 18725-1-AP, China), P62 (proteintech, 66184-1-Ig, China), Beclin1 (proteintech, 66665-1-Ig, China), AKT (CST, 9272S, USA), Phospho-AKT (Ser473) (Beyotime, AA329, China), mTOR (CST, 2972S, USA), Phospho-mTOR (S2448) (Boster, BM4840, China), p70S6K (Bioss, bs-6370R, China), Phospho-p70S6K (Ser417) (Bioss, bs-5668R, China), GAPDH (proteintech, 60004-1-Ig, China), β-Actin (proteintech, 20536-1-AP, China), goat anti-rabbit immunoglobulin G (IgG) (H+L)-horseradish Peroxidase (HRP; proteintech, SA00001-2, China), goat anti-mouse IgG (H+L)-HRP (OriGene proteintech, SA00001-1, China), goat anti-rabbit immunoglobulin G (IgG) ( H+L)-fluorescein (FITC; proteintech, SA00003-2, China)

Animal research

BALB/c nude mice were purchased from Zhejiang Weitong Lihua Bioscience Co., Ltd. 1×10⁷ HCT15 were resuspended in 100 μl PBS and injected subcutaneously into nude mice. When the tumor volume reached 75mm³, the mice were randomly divided into two groups, and the mice were injected intraperitoneally with 100μL (75% saline) or moxidectin (15mg/kg/100μL/day). After 15 days tumor size was measured with a caliper and calculated as volume (mm³) using the equation: V = 0.5 x length x width², all mice were euthanized with ether anesthesia, tumors were dissected and frozen in liquid nitrogen.

Cell viability assay

Cells were seeded in 96-well plates and incubated overnight, then cells were exposed to the indicated concentrations of drug for 36 h. Subsequently, cells were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Briefly, 10 μL MTT was added to each well and incubated for 4 hours. The medium was removed and 150 μL DMSO was added to each well to dissolve the crystalline formazan dye. Absorbance was measured at 490 nm on an enzyme-linked immunosorbent assay (ELX808IU, Bio-Tek).

Lactate dehydrogenase assay

Lactate dehydrogenase (LDH) activity was determined by LDH release kit (Beyotime, C0016). Assays were performed according to the manufacturer's instructions. Briefly, LDH converts pyruvate to lactate, reducing the developer to a colored product with absorbance at 450 nm as measured by an enzyme-linked immunosorbent assay (ELX808IU, Bio-Tek).

Colony Formation Assay

300 cells were seeded in 6-well plates. Cells were cultured continuously for 7 days in the presence or absence of indicated concentrations of moxidectin, CQ, 3-MA. Colonies were stained with crystal violet and counted using a microscope. Only those cell clusters containing more than 50 cells were considered clones.

Flow Cytometry

After washing the harvested cells twice with PBS, resuspend the cells in binding buffer (500 μL) containing 5 μL Annexin V-FITC (Annexin V-FITC Detection Kit C1052, Biyuntian Biotechnology Co., Ltd., Shanghai ,China). Then, 10 μL of propidium iodide (PI) was applied to the suspension and the cells were incubated for an additional 10 min. The degree of apoptosis was determined using an Agilent NovoCyte Cell Analyzer (Agilent, NovoCyte, USA).

Transmission electron microscope

Transmission electron microscopy analysis was used to visualize autophagic vesicles. Briefly, HCT15 and SW620 cells were fixed in 0.1% glutaraldehyde. After dehydration, ultrathin sections were prepared using a Sorvall MT5000 microtome. Samples were stained with lead citrate and/or uranyl acetate. Autophagic vesicles were analyzed by Philips EM420 electron microscope.

Fluorescence quantitative polymerase chain reaction

Total RNA was obtained using Trizol (Thermo Fisher Scientific, 15596018) and total cDNA was generated using the PrimeScript™ RT Kit and gDNA Eraser (Takara, RR047A). Bio-Rad iTaq Universal SYBR Green Supermix (1725271) was then used to quantify the mRNA levels of the indicated genes. The primer pairs used for CFTR were: front 5'-TAGGAGCTTGAGCCCAGACG-3', reverse 5'-AACATCGCCGAAGGGCATTA-3', and the primer pair for GRP78 was front 5'-GCCTGTATTTCTAGACCTGCC-3', reverse 5'-TTCATCTTGCCAGCCAGTTG- 3'.

Immunofluorescence

Cells were seeded onto glass coverslips in 24-well plates. After treatment, cells were fixed with 4% paraformaldehyde in PBS for 30 min. The slides were then washed three times with PBS and incubated with 0.4% Triton X-100 (Sigma-aldrich, 9002-93-1) and 5% goat serum (Sigma-aldrich, G9023) for 30 min. Cells were incubated with LC3B antibody overnight at 4°C, followed by fluorescein-conjugated secondary antibody for 1 hour at 37°C. Nuclei were finally stained with DAPI for 10 min and washed with PBS to stop the reaction. Visualize images using an upright fluorescence microscope.

Tandem mRFP-GFP fluorescence microscopy

Using tandem mRFP-GFP-tagged LC3 plasmids, cells were transfected with the addition of Lipofectamine 3000. After moxidectin treatment, cells were fixed with 4% paraformaldehyde for 30 min and rinsed twice with PBS. Visualize images using an upright fluorescence microscope.

Quantitative and statistical analysis

The analysis was performed using the statistical software package GraphPad Prism 6.0. The obtained data were analyzed using Student's t-test or one-way analysis of variance (ANOVA). Data are expressed as SD±mean, and statistical significance is defined as *P<0.05; **P<0.01; ***P<0.001; ns means no statistical significance。

Acknowledgements This research was funded by Chengdu Medical College Fund, grant number “CYZYB21-18”;

Authors’ contributions KJP and JBLconceived the experiments; YSM performed the experiments and drafted the manuscript; HHX and DS collected sample organization analyzed the data; LC performed the manuscript editing and manuscript reviewing. All authors read and approved the final manuscript

Data availability Data transparency.
Declarations
Conflicts of interest Not applicable.
Ethics approval All animal experimental were approved by the Animal Ethical Committee of Chengdu Medical College (Sichuan, China).
Informed consent Animal experimental have been approved by the Ethical Committee of Chengdu Medical College (Sichuan, China)

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Moxidectin induces lethal autophagy arrest via CFTR

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