Skip to main content

Advertisement

SpringerLink
Log in

Inhibition of PI3K/AKT signaling using BKM120 reduced the proliferation and migration potentials of colorectal cancer cells and enhanced cisplatin-induced cytotoxicity

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Background

Although extensive efforts have been made to improve the treatment of colorectal cancer (CRC) patients, the prognosis for these patients remains poor. A wide range of anti-cancer agents has been applied to ameliorate the clinical management of CRC patients; however, drug resistance develops in nearly all patients. Based on the prominent role of PI3K/AKT signaling in the development of CRC and current interest in the application of PI3K inhibitors, we aimed to disclose the exact mechanism underlying the efficacy of BKM120, a well-known pan-class I PI3K inhibitor, in CRC-derived SW480 cells.

Materials and methods

The effects of BKM120 on SW480 cells were studied using MTT assay, cell cycle assay, Annexin V/PI apoptosis tests, and scratch assay. In the next step, qRT-PCR was used to investigate the underlying molecular mechanisms by which the PI3K inhibitor could suppress the survival of SW480 cells.

Result

The results of the MTT assay showed that BKM120 could decrease the metabolic activity of SW480 cells in a concentration and time-dependent manner. Investigating the exact mechanism of BKM120 showed that this PI3K inhibitor induces its anti-survival effects through a G2/M cell cycle arrest and apoptosis-mediated cell death. Moreover, the scratch assay demonstrated that PI3K inhibition led to the inhibition of cancer invasion and inhibition of PI3K/AKT signaling remarkably sensitized SW480 cells to Cisplatin.

Conclusion

Based on our results, inhibition of PI3K/AKT signaling can be a promising approach, either as a single modality or in combination with Cisplatin. However, further clinical studies should be performed to improve our understanding.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

The authors confirm that the data supporting the findings of this study are available within the article [and/or] its supplementary materials.

References

  1. Xu W, Yu M, Qin J, Luo Y, Zhong M (2020) LACTB regulates PIK3R3 to promote autophagy and inhibit EMT and proliferation through the PI3K/AKT/mTOR signaling pathway in colorectal cancer. Cancer Manage Res 12:5181

    Article  CAS  Google Scholar 

  2. Ciombor KK, Wu C, Goldberg RM (2015) Recent therapeutic advances in the treatment of colorectal cancer. Annu Rev Med 66:83–95

    Article  CAS  PubMed  Google Scholar 

  3. Huh JW, Kim HR, Kim YJ, Lee JH, Park YS, Cho SH, Joo JK (2009) Expression of standard CD44 in human colorectal carcinoma: association with prognosis. Pathol Int 59(4):241–246

    Article  CAS  PubMed  Google Scholar 

  4. El Bali M, Bakkach J, Bennani Mechita M (2021) Colorectal cancer: from genetic landscape to targeted therapy. Journal of Oncology. ;2021

  5. Asati V, Mahapatra DK, Bharti SK (2016) PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways inhibitors as anticancer agents: structural and pharmacological perspectives. Eur J Med Chem 109:314–341

    Article  CAS  PubMed  Google Scholar 

  6. Li Q, Lai Z, Yan Z, Peng J, Jin Y, Wei L, Lin J (2018) Hedyotis Diffusa Willd inhibits proliferation and induces apoptosis of 5–FU resistant colorectal cancer cells by regulating the PI3K/AKT signaling pathway. Mol Med Rep 17(1):358–365

    CAS  PubMed  Google Scholar 

  7. Wang Q, Shi Y-l, Zhou K, Wang L-l, Yan Z-x, Liu Y-l, Xu L-l (2018) Zhao S-w, Chu H-l, Shi T-t. PIK3CA mutations confer resistance to first-line chemotherapy in colorectal cancer. Cell Death Dis 9(7):739

    Article  PubMed  PubMed Central  Google Scholar 

  8. Bratton MR, Duong BN, Elliott S, Weldon CB, Beckman BS, McLachlan JA, Burow ME (2010) Regulation of ERα-mediated transcription of Bcl-2 by PI3K-AKT crosstalk: implications for breast cancer cell survival. Int J Oncol 37(3):541–550

    CAS  PubMed  Google Scholar 

  9. Alzahrani AS (ed) (2019) Editor PI3K/Akt/mTOR inhibitors in cancer: at the bench and bedside. Seminars in cancer biology. Elsevier

  10. Yang J, Nie J, Ma X, Wei Y, Peng Y, Wei X (2019) Targeting PI3K in cancer: mechanisms and advances in clinical trials. Mol Cancer 18(1):1–28

    Article  PubMed  PubMed Central  Google Scholar 

  11. André F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, Iwata H, Conte P, Mayer IA, Kaufman B (2019) Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer. N Engl J Med 380(20):1929–1940

    Article  PubMed  Google Scholar 

  12. Yuan M, Huang L-L, Chen J-H, Wu J, Xu Q (2019) The emerging treatment landscape of targeted therapy in non-small-cell lung cancer. Signal Transduct Target Therapy 4(1):61

    Article  Google Scholar 

  13. Malinowsky K, Nitsche U, Janssen K, Bader F, Späth C, Drecoll E, Keller G, Höfler H, Slotta-Huspenina J, Becker K (2014) Activation of the PI3K/AKT pathway correlates with prognosis in stage II colon cancer. Br J Cancer 110(8):2081–2089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Koul D, Shen R, LaFortune TA, Tiao N, Kim Y-W, Liu J-L, Maira S-M, Garcia-Echeverria C, Yung WA (2010) NVP-BKM120: a selective pan-PI3 kinase inhibitor induces G2/M arrest in glioma cell lines via FOXO3a and GADD45a loop. Cancer Res 70(8Supplement):350

    Article  Google Scholar 

  15. Schnell CR, Arnal S, Becquet M, Allegrini P, Voliva C, Cozens R, Garcia-Echeverria C, Maira SM (2010) NVP-BKM120, a pan class I PI3K inhibitor impairs microvascular permeability and tumor growth as detected by DCE-MRI and IFP measurements via radio-telemetry: comparison with NVP-BEZ235. Cancer Res 70(8Supplement):4472

    Article  Google Scholar 

  16. Maira M, Menezes D, Pecchi S, Shoemaker K, Burger M, Schnell c, Fritsch c, Brachmann S, Nagel T, Sellers WR (2010) NVP-BKM120, a novel inhibitor of phosphoinosotide 3-kinase in Phase I/II clinical trials, shows significant antitumor activity in xenograft and primary tumor models. Cancer Research. ;70(8_Supplement):4497-

  17. Voliva cF, Pecchi S, Burger M, Nagel T, Schnell C, Fritsch c, Brachmann s, Menezes D, Knapp M, Shoemaker K (2010) Biological characterization of NVP-BKM120, a novel inhibitor of phosphoinosotide 3-kinase in Phase I/II clinical trials. Cancer Research. ;70(8_Supplement):4498-

  18. Campone M, Im S-A, Iwata H, Clemons M, Ito Y, Awada A, Chia S, Jagiełło-Gruszfeld A, Pistilli B, Tseng L-M (2018) Buparlisib plus fulvestrant versus placebo plus fulvestrant for postmenopausal, hormone receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer: overall survival results from BELLE-2. Eur J Cancer 103:147–154

    Article  CAS  PubMed  Google Scholar 

  19. Pistilli B, Pluard T, Urruticoechea A, Farci D, Kong A, Bachelot T, Chan S, Han H, Jerusalem G, Urban P (2018) Phase II study of buparlisib (BKM120) and trastuzumab in patients with HER2 + locally advanced or metastatic breast cancer resistant to trastuzumab-based therapy. Breast Cancer Res Treat 168:357–364

    Article  CAS  PubMed  Google Scholar 

  20. Zhang J, Roberts TM, Shivdasani RA (2011) Targeting PI3K signaling as a therapeutic approach for colorectal cancer. Gastroenterology 141(1):50–61

    Article  CAS  PubMed  Google Scholar 

  21. Massacesi C, Di Tomaso E, Urban P, Germa C, Quadt C, Trandafir L, Aimone P, Fretault N, Dharan B, Tavorath R (2016) PI3K inhibitors as new cancer therapeutics: implications for clinical trial design. OncoTargets Therapy. :203–210

  22. Shiri Heris R, Safaroghli-Azar A, Yousefi AM, Hamidpour M, Bashash D (2020) Anti‐leukemic effect of PI3K inhibition on chronic myeloid leukemia (CML) cells: shedding new light on the mitigating effect of c‐Myc and autophagy on BKM120 cytotoxicity. Cell Biol Int 44(5):1212–1223

    Article  CAS  PubMed  Google Scholar 

  23. Zabihi M, Lotfi R, Yousefi A-M, Bashash D (2022) Cyclins and cyclin-dependent kinases: from biology to tumorigenesis and therapeutic opportunities. J Cancer Res Clin Oncol. :1–22

  24. Debnath J, Baehrecke EH, Kroemer G (2005) Does autophagy contribute to cell death? Autophagy 1(2):66–74

    Article  CAS  PubMed  Google Scholar 

  25. Wang RC, Wei Y, An Z, Zou Z, Xiao G, Bhagat G, White M, Reichelt J, Levine B (2012) Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science 338(6109):956–959

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  26. Jiang QG, Li TY, Liu DN, Zhang HT (2014) PI3K/Akt pathway involving into apoptosis and invasion in human colon cancer cells LoVo. Mol Biol Rep 41:3359–3367

    Article  CAS  PubMed  Google Scholar 

  27. Hammond WA, Swaika A, Mody K (2016) Pharmacologic resistance in colorectal cancer: a review. Therapeutic Adv Med Oncol 8(1):57–84

    Article  CAS  Google Scholar 

  28. Carr KM, Rosenblatt K, Petricoin EF, Liotta LA (2004) Genomic and proteomic approaches for studying human cancer: prospects for true patient-tailored therapy. Hum Genomics 1(2):1–7

    Article  Google Scholar 

  29. Wen F, He S, Sun C, Li T, Wu S (2014) PIK3CA and PIK3CB expression and relationship with multidrug resistance in colorectal carcinoma. Int J Clin Exp Pathol 7(11):8295

    PubMed  PubMed Central  Google Scholar 

  30. Bahrami A, Khazaei M, Hasanzadeh M, ShahidSales S, Joudi Mashhad M, Farazestanian M, Sadeghnia HR, Rezayi M, Maftouh M, Hassanian SM (2018) Therapeutic potential of targeting PI3K/AKT pathway in treatment of colorectal cancer: rational and progress. J Cell Biochem 119(3):2460–2469

    Article  CAS  PubMed  Google Scholar 

  31. Yap TA, Bjerke L, Clarke PA, Workman P (2015) Drugging PI3K in cancer: refining targets and therapeutic strategies. Curr Opin Pharmacol 23:98–107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mayer IA, Abramson VG, Isakoff SJ, Forero A, Balko JM, Kuba MG, Sanders ME, Yap JT, Van den Abbeele AD, Li Y (2014) Stand up to cancer phase ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 32(12):1202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Geuna E, Milani A, Martinello R, Aversa C, Valabrega G, Scaltriti M, Montemurro F (2015) Buparlisib, an oral pan-PI3K inhibitor for the treatment of breast cancer. Expert Opin Investig Drugs 24(3):421–431

    Article  CAS  PubMed  Google Scholar 

  34. Vansteenkiste JF, Canon J-L, De Braud F, Grossi F, De Pas T, Gray JE, Su W-C, Felip E, Yoshioka H, Gridelli C (2015) Safety and efficacy of buparlisib (BKM120) in patients with PI3K pathway-activated non-small cell lung cancer: results from the phase II BASALT-1 study. J Thorac Oncol 10(9):1319–1327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Clarke J, Armstrong A (2013) Novel therapies for the treatment of advanced prostate cancer. Curr Treat Options Oncol 14:109–126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mueller A, Bachmann E, Linnig M, Khillimberger K, Schimanski CC, Galle PR, Moehler M (2012) Selective PI3K inhibition by BKM120 and BEZ235 alone or in combination with chemotherapy in wild-type and mutated human gastrointestinal cancer cell lines. Cancer Chemother Pharmacol 69:1601–1615

    Article  CAS  PubMed  Google Scholar 

  37. Koul D, Fu J, Shen R, LaFortune TA, Wang S, Tiao N, Kim Y-W, Liu J-L, Ramnarian D, Yuan Y (2012) Antitumor activity of NVP-BKM120—a selective pan class I PI3 kinase inhibitor showed differential forms of cell death based on p53 status of glioma cells. Clin Cancer Res 18(1):184–195

    Article  CAS  PubMed  Google Scholar 

  38. Roy SK, Srivastava RK, Shankar S (2010) Inhibition of PI3K/AKT and MAPK/ERK pathways causes activation of FOXO transcription factor, leading to cell cycle arrest and apoptosis in pancreatic cancer. J Mol Signal 5(1):1–13

    Google Scholar 

  39. Zhang W, Feng Y, Guo Q, Guo W, Xu H, Li X, Yi F, Guan Y, Geng N, Wang P (2020) SIRT1 modulates cell cycle progression by regulating CHK2 acetylation – phosphorylation. Cell Death Differ 27(2):482–496

    Article  PubMed  Google Scholar 

  40. Civallero M, Cosenza M, Sacchi S (2014) New targets and potential strategy to enhance the Anticancer Efficacy BKM-120 and BEZ235 in Lymphoma Cell lines. Blood 124(21):1773

    Article  Google Scholar 

  41. El-Shafey ES, Elsherbiny ES (2020) Dual opposed survival-supporting and death-promoting roles of autophagy in cancer cells: a concise review. Curr Chem Biol 14(1):4–13

    Article  CAS  Google Scholar 

  42. Mizushima N, Yoshimori T, Ohsumi Y (2011) The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol 27:107–132

    Article  CAS  PubMed  Google Scholar 

  43. Ming H, Li B, Zhou L, Goel A, Huang C (2021) Long non-coding RNAs and cancer metastasis: molecular basis and therapeutic implications. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer. 1875(2):188519

  44. Sinnberg T, Lasithiotakis K, Niessner H, Schittek B, Flaherty KT, Kulms D, Maczey E, Campos M, Gogel J, Garbe C (2009) Inhibition of PI3K-AKT-mTOR signaling sensitizes melanoma cells to cisplatin and temozolomide. J Invest Dermatology 129(6):1500–1515

    Article  CAS  Google Scholar 

  45. Jiang W, Yan Y, Chen M, Luo G, Hao J, Pan J, Hu S, Guo P, Li W, Wang R (2020) Aspirin enhances the sensitivity of colon cancer cells to cisplatin by abrogating the binding of NF-κB to the COX-2 promoter. Aging 12(1):611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to express their gratitude to Shahid Beheshti University of Medical Sciences (Tehran, Iran) for supporting this study.

Author information

Authors and Affiliations

  1. Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran

    Sepideh Chodary Khameneh & Soyar Sari

  2. Department of Biology, School of Basic Science, Science and Research Branch, Islamic Azad University, Tehran, Iran

    Sara Razi

  3. Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Amir-Mohammad Yousefi & Davood Bashash

Authors
  1. Sepideh Chodary Khameneh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Soyar Sari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sara Razi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amir-Mohammad Yousefi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Davood Bashash
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Davood Bashash.

Ethics declarations

Ethical approval

This article does not contain any studies with human participants performed by any of the authors.

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Khameneh, S.C., Sari, S., Razi, S. et al. Inhibition of PI3K/AKT signaling using BKM120 reduced the proliferation and migration potentials of colorectal cancer cells and enhanced cisplatin-induced cytotoxicity. Mol Biol Rep 51, 420 (2024). https://doi.org/10.1007/s11033-024-09339-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11033-024-09339-2

Keywords

Search

Navigation