SRT3025-loaded cell membrane hybrid liposomes enhanced anti-carcinoma activity of Oxaliplatin via inhibiting pyruvate kinase M2 and fatty acid synthase

doi:10.21203/rs.3.rs-4691639/v1

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Research Article

SRT3025-loaded cell membrane hybrid liposomes enhanced anti-carcinoma activity of Oxaliplatin via inhibiting pyruvate kinase M2 and fatty acid synthase

https://doi.org/10.21203/rs.3.rs-4691639/v1

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Background

Bladder cancer is one of the most common malignancies of the urinary system, and despite significant advances in diagnosis and treatment, oxaliplatin resistance remains a major clinical challenge. Thus, developing a novel delivery system is required to overcome oxaliplatin resistance and improve patient outcomes.

Methods

Bladder cancer cell lines, T24 and 5637, were cultured in McCoy’s 5A and RPMI 1640 medium, respectively. The phospholipids and cell membranes were used to formulate the hybrid liposomes. Cell Counting Kit-8 assay was used to determine the cell viability and proliferation. Cell death and apoptosis were quantified by trypan blue, calcein-AM/PI double staining, and Annexin V-APC/PI apoptosis assay. Western blot analysis was used to determine the proteins level.

Results

The present study demonstrated that SRT3025-loaded cell membrane hybrid liposomes (3025@ML) enhance the chemosensitivity to oxaliplatin (OXA). 3025@ML monotherapy as well as the combination therapy, 3025@ML plus OXA significantly enhanced the anti-carcinoma activity of OXA. In mechanistic studies, 3025@ML inhibited the PI3K/AKT/mTOR signaling pathway and reduced the expression of key metabolic regulators PKM2 and FASN. Furthermore, this study demonstrated that targeting lipid metabolism and inhibiting FASN can effectively overcome oxaliplatin resistance.

Conclusion

The study demonstrated that SRT3025-loaded cell membrane hybrid liposomes significantly enhance the anti-tumor activity of OXA. This novel drug delivery system inhibits key metabolic pathways, increasing DNA damage and tumor cell apoptosis. The results suggest that 3025@ML is a promising therapeutic strategy for overcoming oxaliplatin resistance and improving cancer treatment outcomes.

Bladder cancer

SRT3025

Oxaliplatin

PKM2

FASN

Bladder cancer (BC) is the most common malignant tumor of the urinary system [1]. Although surgical resection significantly prolongs the survival time of patients, some of them still experience tumor recurrence within 5 years [2]. Therefore, chemotherapy is still the most common treatment therapy for these patients with unresectable tumors. Currently, oxaliplatin (OXA) is the most commonly used chemotherapy drug for the treatment of tumors. However, the natural and acquired resistance to OXA is the reason for the poor treatment of OXA [3]. Overcoming OXA resistance is urgently required for effective OXA treatment.

OXA, as a third-generation platinum, binds to DNA after entering tumor cells to form a hairpin-like structure, causing DNA damage and thus inducing cell death. It is worth noting that it has been proven that targeting the metabolism of tumor cells without causing toxicity to normal cells is a potential strategy for treating cancer [4]. Indeed, some studies demonstrated that inhibition of the activity of pyruvate kinase M2 (PKM2), a member of pyruvate kinase controlling cell metabolism, enhances the anti-carcinoma activity of chemotherapy [5].

Fatty acid synthase (FASN) is a multifunctional enzyme crucial in synthesizing long-chain saturated fatty acids, particularly palmitic acid, within cells. The activity of FASN is essential for cellular lipid metabolism, providing fatty acids necessary for several vital processes, such as cell membrane synthesis, energy storage and signaling molecule synthesis. Recent studies proved that FASN was regulated by PKM2 and involved in the chemoresistant [6, 7].

SRT3025 is a member of SIRT1-activating compounds (STACs) and shows excellent anti-tumor effects [8]. Tae et al. reported that inhibition of SIRT1 by MHY2245, a new SIRT1 inhibitor, decreased the level of PKM2 and blocked the energy metabolism in human ovarian cancer cells [9]. However, no study has reported the relationship between SRT3025 and PKM2. Additionally, it is reported that nanomedicines offer significant advantages in tumor treatment by protecting the drugs, enhancing their accumulation and penetration within tumor tissues, and minimizing adverse reactions in normal tissues [10]. These benefits underscore the promising future of nanomedicines in oncology.

Therefore, SRT3025-loaded cell membrane hybrid liposomes (3025@ML) were developed in this study, and the benefit of 3025@ML in overcoming Oxaliplatin resistance was evaluated. In addition, the effects of PKM2 and FASN in Oxaliplatin resistance were also investigated.

Cell culture and reagents

The bladder cells lines T24 cells and 5637 cells were cells purchased from Cell Bank/Stem Cell Bank (Chinese Academy of Sciences, Beijing, China) have been cultured in McCoy's 5a medium (Thermo Fisher Scientific, Waltham, MA, USA, catalog no. 16600082) or RPMI 1640 medium (Thermo Fisher Scientific, Waltham, catalog no. 11875093) with 10% fetal bovine serum (FBS, AusGeneX, Gold Coast, Australia, catalog no. FBS500-S). Oxaliplatin (OXA, catalog no. S1224), SRT3025 (catalog no. S8481) and compound 3K (3K, catalog no. S8616) were purchased from Selleck Chemicals (Houston, USA) was obtained from Sigma-Aldrich (St. Louis, USA, catalog no.C6628).

Evaluating cell viability and proliferation

T24 and 5637 cells were seeded at a density of 2.0 × 10³ cells per well in a 96-well plate to assess cell viability. After 24 hours of incubation, the cells were treated with a medium containing either the vehicle solution (Control) or varying concentrations (0.1, 1, 10, 100µM) of SRT3025 or compound 3K for 48 hours. Cell viability was evaluated using the Cell Counting Kit-8 (CCK8, MedChemExpress, Monmouth Junction, USA, code HY-K0301). This assay utilizes WST-8, a water-soluble tetrazolium salt that is reduced to formazan by cellular dehydrogenases in viable cells. The reduction results in a color change from yellow to orange, directly proportional to the number of living cells. To evaluate the effect of the combination on cell proliferation, cells were plated as described above and treated with OXA, SRT3025-loaded cell membrane hybrid liposomes (3025@ML), compound 3K, or the combination. The intensity of the color change was quantified by measuring the absorbance at 450 nm using a Synergy LX multimode reader (BioTek, Winooski, USA).

Evaluating cell death

3.0 × 10⁴ T24 and 5637 cells were seeded per well in a 24-well plate for 24 hours to evaluate cell death. Subsequently, these cells were treated with Control or different formulations for 48 hours. Cell death was quantified by staining with the trypan blue and the calcein-AM/PI double stain kit (Yeasen, Shanghai, China, code 40747ES76) with Axio Vert. A1 fluorescence microscope (Carl Zeiss, Oberkochen, Germany).To investigate the apoptosis, T24 cells were seeded at a density of 2.5 × 10⁵ cells per well in a 6-well plate and treated with Control, 3025@ML, OXA or a combination of both drugs for 48 hours. Apoptotic cells were quantified using the Annexin V-APC/PI apoptosis kit (Elabscience, Houston, USA, catalog no. E-CK-A217) and a NovoCyte flow cytometer system (Agilent, Santa Clara, USA).

Western blot

To determine the level of pyruvate kinase M2 (PKM2), fatty acid synthase (FASN) and the regulation of apoptosis protein, such as BCL2-Associated X (Bax), B-cell lymphoma-2 (Bcl-2) and cleaved caspase-3. 2.5 × 10⁵ T24 and 5637 cells were seeded per well in a 6-well plate separately and cultured for 24 hours. These cells were treated with the appropriate drug for 48 hours. After lysis with RIPA lysis Buffer, samples were centrifugated at 10000× g for 30 min at 4℃. The supernatant was collected, the protein concentration determined, and the proteins were denatured by boiling in an SDS-gel loading buffer for 10 min. Equal amounts of protein were subjected to 15% SDS-PAGE. Proteins were blotted onto PVDF Western blotting membranes (Roche Diagnostics, Mannheim, Germany) and incubated with antibody against using the following antibodies: Anti-PKM2 antibody (PKM2, Cell Signaling Technology, Danvers, MA, USA, catalog no. 4053, dilution: 1000 ×) Anti-Bax antibody (Bax, Abcam, Cambridge, UK, catalog no. ab32503, dilution: 1000 ×), Anti-Bcl-2 antibody (Bcl-2, Abcam, catalog no. ab32124, dilution: 1000 ×), anti-Cleaved Caspase-3 antibody (Cleaved Caspase-3, Cell Signaling Technology, catalog no. 9661, dilution: 1000 ×), anti-fatty acid synthase antibody (FASN, Cell Signaling Technology, catalog no. 3180, dilution: 1000 ×), anti-phospho-protein kinase B antibody (P-AKT, Cell Signaling Technology, code #9271S, dilution: 1000×), anti-protein kinase B antibody (T-AKT, Cell Signaling Technology, code #9272S, dilution:1000×), anti-phospho-mammalian target of rapamycin antibody (p-mTOR, Abcam, code #ab109268, 1000×), anti-mammalian target of rapamycin antibody (T-mTOR, Abcam, code #ab2732, 1000×) and anti-β-actin antibody (Sigma-Aldrich, St. Louis, USA, catalog no. A3854, dilution: 50000×). The proteins were visualized with horseradish peroxidase-conjugated goat anti-rabbit IgG (Cell Signaling, Danvers, USA, catalog no. 7074) by using a Thermo Scientific SuperSignal West Femto Maximum Sensitivity Substrate (Waltham, USA, catalog no. 34096).

Synthesis of the 3025@ML

To synthesize 3025@ML, we initially dissolved 1,2-Dimyristoyl-sn-glycero-3- phosphocholine (DMPC, Avantor Inc., Radnor, PA, USA, catalog no. S01003), 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC, Avantor Inc., catalog no. S01004), DSPE-MPEG2000 (Avantor Inc., catalog no. F01008) and SRT3025 in a mixture of chloroform and methanol (9:1, v/v) and vortexed, later the organic solution was removed through rotary evaporation at 37℃, 30 rpm under reduced pressure. On the formation of a lipid film on the bottom wall of the flask, PBS was added to form a biphasic system and kept in a rotary evaporator at 45℃ and 60rpm for 30 minutes. The resulting suspension was sonicated in an ultrasonic cell crusher for 2 minutes in an ice water bath to yield the 3025@L. Cell membrane vesicles were harvested and extracted from T24 cells as previously reported by Zhang et al [11]. These membranes were incubated with 3025@L 37℃ for 15 minutes, followed by ultrasonication on ice for 3 minutes to ensure the complete fusion of the liposome (Lipo) and tumor membrane (Mem), resulting in 3025@ML. Dio-Lipo and Dil-Mem were prepared by substituting Dio-liposome and Dil-tumor membranes with the process similar to 3025@ML.

Characterization of the 3025@M

To evaluate the stability of nanoparticles, the size distribution and zeta potential of the nanoparticles were determined by Zetatronix 919 (Opptronix, Shanghai, China). To verify if we successfully developed the cell membrane hybrid liposomes (ML), Dio-Lipo and Dil-Mem was evaluated by colocalization analysis with the help of an Axio Vert. A1 fluorescence microscope (Carl Zeiss, Oberkochen, Germany). In addition, samples, including Lipo, Mem, and ML, were added to the SDS gel loading buffer for lysis and boiling. Subsequently, gels were stained with Coomassie brilliant blue to observe membrane protein expression. To examine the cytotoxicity of nanoparticles, 4 × 10³ T24 and 5637 cells were seeded per well in a 96-well plate separately and cultured for 24 hours. The cells were treated with different nanoparticle concertations following 48 hours. CCK8 assay detected the cytotoxicity of Lipo, Mem and ML.

Drug loading capacity and encapsulation efficiency

SRT3025 was dissolved in methanol. The maximum absorption wavelength of SRT3025 was determined using ultraviolet-visible (UV-Vis) scanning spectroscopy. The solution was scanned with a UV-Vis spectrophotometer over 200 nm to 800 nm, and then diluted to gradient concentrations of 100 µg/ml, 60 µg/ml, 20 µg/ml, 10µg/ml and 1µg/ml to create a standard curve for SRT3025. To determine the drug loading capacity, various ratios of 3025@ML were synthesized. Drug Loading Capacity (DLC) and Encapsulation Efficiency (EE) were calculated using the following formulas:

DLC(%) = m _{drug in ML}/(m _{total drug} + m _ML) × 100%

EE(%) = m _{drug in ML}/m _{total drug} × 100%

Statistical analysis

The date are presented as means ± SD (error bars). GraphPad Prism software was used to analyze the date. The Mann-Whitney rank sum test was performed to evaluate the significant differences, and a P value lower than 0.05 was considered significant.

Synthesis and characterization of 3025@ML

The thin film hydration method was used to develop 3025@ML (Fig. 1A). The diameter of Lipo, Mem and ML was approximately 100 ~ 200 nm (Fig. 1B), and the zeta potential of ML was similar to Mem (Fig. 1C). To observe the Mem coating on Lipo, Mem and Lipo were labelled with Dil and Dio dyes respectively and analyzed by fluorescence co-localization. Yellow fluorescent signals produced by superimposition of red fluorescent Dil-Mem and green fluorescent Dio-Lipo were observed (Fig. 1D). In addition, membrane proteins were determined by SDS-page gel and Coomassie Brilliant Blue reagent. Compared with Lipo, Mem and ML carriers have proteins (Fig. 1E), which indicates that tumor cell membrane-modified liposome nanocarriers were successfully synthesized. To study whether ML affects the viability of bladder cancer cells, we used different concentrations of ML carriers and cell viability was measured in T24 and 5637 cells by CCK8 assay. It was observed that ML did not significantly affect the growth of tumor cells (Fig. 1F), indicating that ML is biocompatible. The UV spectrum of the SRT3025 methanol solution was scanned, and the maximum absorption was detected at a wavelength of 295 nm (Fig. 1G). In order to prepare a standard curve of SRT3025, different concentrations of SRT3025 were prepared, and the absorbance value was detected at a wavelength of 295 nm. We determined that drug loading capacity and encapsulation efficiency were higher at the mass ratio of SRT3025:ML, which is 1:1 (Fig. 1I and J).

3025@ML inhibited PKM2 expression and induced cell apoptosis

To determine the optimal dose of 3025@ML for in vitro studies, T24 and 5637 cells were treated with 0, 1, 10, 100 and 1000µM 3025@ML for 48 hours (Fig. 2A and B). The results showed that 3025@ML significantly reduced the cell viability of both cell types in a dose-dependent manner. To analyze the mechanism of the anti-tumor effect of 3025@ML, bladder cancer cells were treated with 3025@ML, and western blot was used to detect the expression of PKM2 protein and the key proteins of the apoptosis signaling pathway, Bax, Bcl-2 and Cleaved Caspase-3. 3025@ML down-regulated the expression of PKM2 and activated the apoptosis pathway, promoting cell apoptosis.

Compound 3K downregulated PKM2 level to enhance anti-tumor activity of OXA

In order to evaluate the activity of PKM2 in regulating apoptosis. The effect of compound 3K, a traditional inhibitor of PMK2 on cell proliferation was determined by using a CCK8 to test cell viability. T24 and 5637 cells were treated with different concentrations of compound 3K for 48 hours (Fig. 3A). The result showed that compound 3K significantly inhibited the cell viability of T24 and 5637 cells. 10µM compound 3K was combined with OXA to administer to two bladder cancer cell lines (Fig. 3B and C). Compared with the two single-drug groups, Compound 3K significantly increased the chemosensitivity of OXA. In order to examine the relationship between PMK2 and lipid metabolism, PMK2 and FASN were detected by western blot (Fig. 3D and E). This indicates that compound 3K inhibited the expression of PKM2 and FASN and induced cell apoptosis pathway, thereby promoting cell apoptosis.

3025@ML enhanced anti-carcinoma activity of OXA

To explore whether 3025@ML increases the chemotherapy sensitivity of OXA, 3025@ML was combined with OXA to treat T24 and 5637 cell lines. CCK8 was used to detect the cell viability (Fig. 4A and B), and trypan blue reagent staining (Fig. 4C and D) was used to detect the cell death rate. The results showed that combined treatment significantly reduced cell viability and significantly increased cell death rate. Flow cytometry analysis showed that 3025@ML combined with OXA significantly increased the percentage of apoptotic cells in T24 cells (Fig. 4E). In order to investigate the mechanism of 3025@ML combined with OXA to promote cell death, western blot was performed which showed that the combination reduced PKM2 protein, thereby reducing FASN protein and activating the AKT/mTOR signaling pathway (Fig. 4F).

The present study proved that (3025@ML) increased the anti-tumor effect of OXA by impairing the activity of the PI3K/AKT/mTOR signaling pathway and decreasing the expression of PKM2 and FASN.

Lipid metabolism includes fatty acid synthesis, oxidation, and lipid transport, which carries lipids from the liver to peripheral tissues or back to the liver through lipoproteins [12]. It is reported that elevated fatty acid synthesis activity was observed in several cancer cells resistant to chemotherapy. Wang et al. reported that the receptor of long-chain free fatty acids (FFAs), G protein-coupled receptor 120 (GPR120), was highly expressed in primary breast cancer treated by chemotherapy. The in vitro and in vivo study demonstrated that GPR120 increases to the expression of Acetyl CoA carboxylase, sterol regulatory element-binding transcription factor 1, sterol regulatory element-binding transcription factor 2 and FASN and induced the resistance of breast cancer cells to chemical drugs [13]. Indeed, in the present study, we also observed that 3025@ML and Compound 3K, the inhibitor of PKM2, reduced the level of FASN in T24 and 5637 cells and increased the anti-tumor activity of OXA. These studies suggest that targeting FASN is a promising strategy to overcome the chemoresistant. Although a clinical study demonstrated that omeprazole, a proton pump inhibitor, was tolerable and inhibited the expression of FASN, no study proved that inhibition of FASN significantly prolonged the survival of patients [14]. Therefore, a randomized controlled trial is needed to evaluate the benefits of chemical drugs and inhibitors of FASN in treating cancer patients.

STACs are chemical compounds, such as SRT2183, SRT3025 and SRT1720, that influence the activity of sirtuins, a class of enzymes that utilize NAD⁺ to deacetylate proteins. At the beginning of this study, the CCK8 experiment proved that the anti-tumor activity of SRT3025 was significantly potent than SRT2183 and SRT1720 in bladder cancer cells; we therefore evaluated the benefit of SRT3025 and OXA in treating T24 and 5637 cells (data not shown). Previous studies proved that nano-drug delivery technology could significantly enhance the cellular uptake of drugs by improving drug stability and solubility, thereby enhancing the anti-tumor effect of drugs [15]. Cell membrane hybrid liposome (ML) is an innovative nanocarrier combining natural cell membranes' advantages with synthetic liposome's structural benefits [16]. Compared to the traditional liposome, ML is covered by cell membranes, which helps the nanoparticle evade surveillance and elimination by the immune system. Therefore, we developed SRT3025-loaded cell membrane hybrid liposomes (3025@ML), and we observed that 3025@ML significantly increased the activity of OXA.

Although STACs are considered the activator of the SIRT1 enzyme, numerous studies have proved that the anti-tumor activity of STACs does not rely solely on the activation of SIRT1. For example, Dirk Beher et al. proved that resveratrol, which is claimed to be a traditional SIRT1 activator, failed to acetylate peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), although SIRT1 deacetylates PGC-1α [17]. In the present study, Western blot proved that 3025@ML enhanced the effect of OXA by inhibiting the activity of PKM2 and FASN. A previous study reported that metformin decreased the accumulation of PKM2 by suppressing the PI3K/AKT/mTOR signaling pathway in esophageal cancer cells [18]; we, therefore, determined the activity of PI3K/AKT/mTOR axis after treating the cells by 3025@ML. The results demonstrated that 3025@ML decreased p-PI3K, p-AKT, p-mTOR and PKM2 levels. These data also suggested that the level of PKM2 was regulated by the PI3K/AKT/mTOR axis.

There are some limitations in the present study. First, although Compound 3K, the traditional inhibitor of PKM2, and 3025@ML decrease the accumulation of FASN and significantly enhance the anti-tumor activity of OXA, further study still needs to clarify how PKM2 regulates the expression of FASN. This will prove novel regulators of FASN and accelerate the drug development process for bladder cancer. Second, no study has investigated the benefit of 3025@ML in combination with other chemical drugs, such as gemcitabine, methotrexate, and docetaxel, which are also used to treat bladder cancer. Future studies also need to evaluate this.

In conclusion, 3025@ML effectively enhance OXA's anti-tumor activity by targeting PI3K/AKT/mTOR axis to downregulate PKM2 and FASN proteins level. This novel formulation reduces PKM2 and FASN expression, overcoming resistance mechanisms and enhancing therapeutic efficacy. Further studies should therefore be elucidate the regulatory mechanisms and explore potential synergies with other chemotherapeutic agents for broader clinical applications in cancer treatment.

OXA

Oxaliplatin

3025@ML

SRT3025 loaded cell membrane hybrid liposomes

PKM2

pyruvate kinase M2

FASN

fatty acid synthase

STACs

SIRT1-activating compounds

Bax

BCL2-Associated X

Bcl-2

B-cell lymphoma-2

PI3K

phosphatidylinositol 3-kinase

AKT

protein kinase B

mTOR

mammalian target of rapamycin

Compound 3K

Availability of data and materials

The data are available from the corresponding author on reasonable request.

Acknowledgements

We thank BioRender (https://app.biorender.com) for assisting with Figure 1 in the manuscript.

Funding

This study was supported by Sanming Project of Medicine in Shenzhen Nanshan (SZSM202103003); Major Scientific and Technological Project of the Health System in Nanshan Shenzhen（NSZD2024062）

Contributions

Xiaobin Wang: Funding acquisition, Methodology, Writing – original draft. Shulin Li: Data curation, Formal analysis, Experimental part .Zichen Li: Writing – review & editing. Zhuona Lin: Methodology. Zhifeng Wang: Project administration, Supervision, Writing – review & editing.

Corresponding author

Xiaobin Wang: [email protected]

Department of Urology, Southern University of Science and Technology Hospital, Shenzhen, 518052, China

Zhifeng Wang: [email protected]

Ethics declarations

Not necessary

Consent for publication

All authors read the final version and agree to publish.

Competing interests

The authors declare no competing interests.

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You are reading this latest preprint version

SRT3025-loaded cell membrane hybrid liposomes enhanced anti-carcinoma activity of Oxaliplatin via inhibiting pyruvate kinase M2 and fatty acid synthase

Status:

Version 1

Abstract

Background

Methods

Results

Conclusion

Figures

Introduction

Method

Cell culture and reagents

Evaluating cell viability and proliferation

Evaluating cell death

Western blot

Synthesis of the 3025@ML

Characterization of the 3025@M

Drug loading capacity and encapsulation efficiency

Statistical analysis

Results

Synthesis and characterization of 3025@ML

3025@ML inhibited PKM2 expression and induced cell apoptosis

Compound 3K downregulated PKM2 level to enhance anti-tumor activity of OXA

3025@ML enhanced anti-carcinoma activity of OXA

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1