Targeting transient receptor potential canonical 1 reduces non‑small cell lung cancer chemoresistance and stemness via inhibition of PI3K/AKT signaling

Jin,Jiahui; Yan,Xinyu; Zhao,Yaru; Zhang,Haojie; Zhuang,Kai; Wen,Yating; He,Jingjing; Gao,Junzhen

doi:10.3892/ol.2023.13810

Targeting transient receptor potential canonical 1 reduces non‑small cell lung cancer chemoresistance and stemness via inhibition of PI3K/AKT signaling

Authors:
- Jiahui Jin
- Xinyu Yan
- Yaru Zhao
- Haojie Zhang
- Kai Zhuang
- Yating Wen
- Jingjing He
- Junzhen Gao
View Affiliations

Affiliations: Department of Oncology, Affiliated Qingdao Central Hospital, Qingdao University, Qingdao, Shandong 266042, P.R. China, Department of Respiratory and Critical Care Medicine, The Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region 010050, P.R. China, Department of Geriatrics, The Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region 010050, P.R. China
Published online on: April 13, 2023 https://doi.org/10.3892/ol.2023.13810
Article Number: 224
Copyright: © Jin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

TRPC1 enhances cell proliferation and migration in non‑small cell lung cancer (NSCLC); however, its effect on NSCLC chemoresistance and stemness remains to be determined. The aim of the current study was to investigate the effect of TRPC1 on NSCLC chemoresistance and stemness and to determine the underlying mechanism of action. Cisplatin‑resistant A549 (A549/CDDP) and H460 (H460/CDDP) cells were first established and were then transfected with negative control small interfering (si)RNA (si‑NC) or TRPC1 siRNA (si‑TRPC1). Cells were then treated with 740 Y‑P, a PI3K/Akt agonist. Subsequently, the sensitivity of A549/CDDP and H460/CDDP cells to CDDP was evaluated. Furthermore, the expression levels of CD133 and CD44, and sphere formation ability were also determined. The results showed that the half‑maximal inhibitory concentration (IC50) of CDDP was significantly higher in A549/CDDP cells compared with A549 cells and in H460/CDDP cells compared with H460 cells. TRPC1 silencing decreased the IC50 value of CDDP compared with the si‑NC group in A549/CDDP (11.78 vs. 21.58 µM; P<0.01) and H460/CDDP (23.76 vs. 43.11 µM; P<0.05) cells. Additionally, TRPC1 knockdown in both cell lines decreased the number of spheres formed compared with the si‑NC group. Furthermore, compared with the si‑NC group, A549/CDDP cells transfected with si‑TRPC1 exhibited decreased levels of both CD133 (P<0.01) and CD44 (P<0.05). However, only CD133 (P<0.05) was downregulated in TRPC1‑depleted H460/CDDP cells compared with the si‑NC group. In addition, TRPC1 knockdown repressed PI3K/AKT signaling compared with the si‑NC group in both A549/CDDP and H460/CDDP cells (all P<0.05). Finally, cell treatment with 740 Y‑P reversed the effect of TRPC1 knockdown on PI3K/AKT signaling, chemoresistance, and cancer stemness in A549/CDDP and H460/CDDP cells (all P<0.05). In conclusion, the results of the current study suggested that targeting TRPC1 could attenuate cancer stemness and chemoresistance via suppression of PI3K/AKT signaling in NSCLC.

View Figures

View References

1	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI
2	Thai AA, Solomon BJ, Sequist LV, Gainor JF and Heist RS: Lung cancer. Lancet. 398:535–554. 2021. View Article : Google Scholar : PubMed/NCBI
3	Rodak O, Peris-Diaz MD, Olbromski M, Podhorska-Okołów M and Dzięgiel P: Current landscape of non-small cell lung cancer: Epidemiology, histological classification, targeted therapies, and immunotherapy. Cancers (Basel). 13:47052021. View Article : Google Scholar : PubMed/NCBI
4	Shah P, Sands J and Normanno N: The expanding capability and clinical relevance of molecular diagnostic technology to identify and evaluate EGFR mutations in advanced/metastatic NSCLC. Lung Cancer. 160:118–126. 2021. View Article : Google Scholar : PubMed/NCBI
5	Chaft JE, Rimner A, Weder W, Azzoli CG, Kris MG and Cascone T: Evolution of systemic therapy for stages I–III non-metastatic non-small-cell lung cancer. Nat Rev Clin Oncol. 18:547–557. 2021. View Article : Google Scholar : PubMed/NCBI
6	Fadejeva I, Olschewski H and Hrzenjak A: MicroRNAs as regulators of cisplatin-resistance in non-small cell lung carcinomas. Oncotarget. 8:115754–115773. 2017. View Article : Google Scholar : PubMed/NCBI
7	de Graeff A, Slebos RJ and Rodenhuis S: Resistance to cisplatin and analogues: Mechanisms and potential clinical implications. Cancer Chemother Pharmacol. 22:325–332. 1988. View Article : Google Scholar : PubMed/NCBI
8	Jing N, Gao WQ and Fang YX: Regulation of formation, stemness and therapeutic resistance of cancer stem cells. Front Cell Dev Biol. 9:6414982021. View Article : Google Scholar : PubMed/NCBI
9	Elzamzamy OM, Penner R and Hazlehurst LA: The role of TRPC1 in modulating cancer progression. Cells. 9:3882020. View Article : Google Scholar : PubMed/NCBI
10	Baudel MASM, Shi J, Large WA and Albert AP: Insights into activation mechanisms of store-operated TRPC1 channels in vascular smooth muscle. Cells. 9:1792020. View Article : Google Scholar : PubMed/NCBI
11	Van den Eynde C, De Clercq K, Van Bree R, Luyten K, Annibali D, Amant F, Han S, Van Nieuwenhuysen E, Baert T, Peeraer K, et al: TRP channel expression correlates with the epithelial-mesenchymal transition and high-risk endometrial carcinoma. Cell Mol Life Sci. 79:262021. View Article : Google Scholar : PubMed/NCBI
12	Tai YK, Chan KKW, Fong CHH, Ramanan S, Yap JLY, Yin JN, Yip YS, Tan WR, Koh APF, Tan NS, et al: Modulated TRPC1 expression predicts sensitivity of breast cancer to doxorubicin and magnetic field therapy: Segue towards a precision medicine approach. Front Oncol. 11:7838032022. View Article : Google Scholar : PubMed/NCBI
13	De Las Rivas J, Brozovic A, Izraely S, Casas-Pais A, Witz IP and Figueroa A: Cancer drug resistance induced by EMT: Novel therapeutic strategies. Arch Toxicol. 95:2279–2297. 2021. View Article : Google Scholar : PubMed/NCBI
14	Pan C, Jin L, Wang X, Li Y, Chun J, Boese AC, Li D, Kang HB, Zhang G, Zhou L, et al: Inositol-triphosphate 3-kinase B confers cisplatin resistance by regulating NOX4-dependent redox balance. J Clin Invest. 129:2431–2445. 2019. View Article : Google Scholar : PubMed/NCBI
15	Tian S, Lou L, Tian M, Lu G, Tian J and Chen X: MAPK4 deletion enhances radiation effects and triggers synergistic lethality with simultaneous PARP1 inhibition in cervical cancer. J Exp Clin Cancer Res. 39:1432020. View Article : Google Scholar : PubMed/NCBI
16	Wang J, Liang J, Li H, Han J, Jiang J, Li Y, Feng Z, Zhao R and Tian H: Oncogenic role of abnormal spindle-like microcephaly-associated protein in lung adenocarcinoma. Int J Oncol. 58:232021. View Article : Google Scholar : PubMed/NCBI
17	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
18	Nesin V and Tsiokas L: TRPC1. Handb Exp Pharmacol. 222:15–51. 2014. View Article : Google Scholar : PubMed/NCBI
19	Zeng YZ, Zhang YQ, Chen JY, Zhang LY, Gao WL, Lin XQ, Huang SM, Zhang F and Wei XL: TRPC1 inhibits cell proliferation/invasion and is predictive of a better prognosis of esophageal squamous cell carcinoma. Front Oncol. 11:6277132021. View Article : Google Scholar : PubMed/NCBI
20	Bomben VC, Turner KL, Barclay TT and Sontheimer H: Transient receptor potential canonical channels are essential for chemotactic migration of human malignant gliomas. J Cell Physiol. 226:1879–1888. 2011. View Article : Google Scholar : PubMed/NCBI
21	Zhang Z, Ren L, Zhao Q, Lu G, Ren M, Lu X, Yin Y, He S and Zhu C: TRPC1 exacerbate metastasis in gastric cancer via ciRS-7/miR-135a-5p/TRPC1 axis. Biochem Biophys Res Commun. 529:85–90. 2020. View Article : Google Scholar : PubMed/NCBI
22	Tajeddine N and Gailly P: TRPC1 protein channel is major regulator of epidermal growth factor receptor signaling. J Biol Chem. 287:16146–16157. 2012. View Article : Google Scholar : PubMed/NCBI
23	Jiang HN, Zeng B, Zhang Y, Daskoulidou N, Fan H, Qu JM and Xu SZ: Involvement of TRPC channels in lung cancer cell differentiation and the correlation analysis in human non-small cell lung cancer. PLoS One. 8:e676372013. View Article : Google Scholar : PubMed/NCBI
24	Hasna J, Hague F, Rodat-Despoix L, Geerts D, Leroy C, Tulasne D, Ouadid-Ahidouch H and Kischel P: Orai3 calcium channel and resistance to chemotherapy in breast cancer cells: The p53 connection. Cell Death Differ. 25:693–707. 2018. View Article : Google Scholar : PubMed/NCBI
25	Tang BD, Xia X, Lv XF, Yu BX, Yuan JN, Mai XY, Shang JY, Zhou JG, Liang SJ and Pang RP: Inhibition of Orai1-mediated Ca²⁺ entry enhances chemosensitivity of HepG2 hepatocarcinoma cells to 5-fluorouracil. J Cell Mol Med. 21:904–915. 2017. View Article : Google Scholar : PubMed/NCBI
26	Sukumaran P, Sun Y, Antonson N and Singh BB: Dopaminergic neurotoxins induce cell death by attenuating NF-κB-mediated regulation of TRPC1 expression and autophagy. FASEB J. 32:1640–1652. 2018. View Article : Google Scholar : PubMed/NCBI
27	Usman RM, Razzaq F, Akbar A, Farooqui AA, Iftikhar A, Latif A, Hassan H, Zhao J, Carew JS, Nawrocki ST and Anwer F: Role and mechanism of autophagy-regulating factors in tumorigenesis and drug resistance. Asia Pac J Clin Oncol. 17:193–208. 2021. View Article : Google Scholar : PubMed/NCBI
28	Ma S, Kong D, Fu X, Liu L, Liu Y, Xue C, Tian Z, Li L and Liu X: p53-induced autophagy regulates chemotherapy and radiotherapy resistance in multidrug resistance cancer cells. Dose Response. 19:155932582110480462021. View Article : Google Scholar : PubMed/NCBI
29	Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O, Castedo M and Kroemer G: Molecular mechanisms of cisplatin resistance. Oncogene. 31:1869–1883. 2012. View Article : Google Scholar : PubMed/NCBI
30	Barbato L, Bocchetti M, Di Biase A and Regad T: Cancer stem cells and targeting strategies. Cells. 8:9262019. View Article : Google Scholar : PubMed/NCBI
31	Yao W, Wang L, Huang H, Li X, Wang P, Mi K, Cheng J, Liu H, Gu C, Huang L and Huang J: All-trans retinoic acid reduces cancer stem cell-like cell-mediated resistance to gefitinib in NSCLC adenocarcinoma cells. BMC Cancer. 20:3152020. View Article : Google Scholar : PubMed/NCBI
32	Pan G, Liu Y, Shang L, Zhou F and Yang S: EMT-associated microRNAs and their roles in cancer stemness and drug resistance. Cancer Commun (Lond). 41:199–217. 2021. View Article : Google Scholar : PubMed/NCBI
33	Xu F, Liu XC, Li L, Ma CN and Zhang YJ: Effects of TRPC1 on epithelial mesenchymal transition in human airway in chronic obstructive pulmonary disease. Medicine (Baltimore). 96:e81662017. View Article : Google Scholar : PubMed/NCBI
34	Zanou N, Schakman O, Louis P, Ruegg UT, Dietrich A, Birnbaumer L and Gailly P: Trpc1 ion channel modulates phosphatidylinositol 3-kinase/Akt pathway during myoblast differentiation and muscle regeneration. J Biol Chem. 287:14524–14534. 2012. View Article : Google Scholar : PubMed/NCBI