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Small molecule ‘4ab’ induced autophagy and endoplasmic reticulum stress-mediated death of aggressive cancer cells grown under adherent and floating conditions

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Abstract

Metastasis is the leading cause of death in cancer patients and a major challenging aspect of cancer biology. Various adaptive molecular signaling pathways play a crucial role in cancer metastasis and later in the formation of secondary tumors. Aggressive cancer cells like triple negative breast cancer (TNBCs) are more inclined to undergo metastasis hence having a high recurrence rate and potential of micro-metastasis. Tumor cells in circulation known as circulating tumor cells (CTCs) offer an attractive drug target to treat metastatic disease. Cell cycle regulation and stress response of CTCs in blood has a crucial role in their survival and progression and thus may be considered therapeutically active hotspots. The cyclin D/cyclin-dependent kinase (CDK) pathway regulates cell cycle checkpoints, a process that is frequently dysregulated in cancer cells. Selective CDK inhibitors can limit the phosphorylation of cell cycle regulatory proteins by inducing cell cycle phase arrest, and thus may be an effective therapeutic strategy for aggressive cancer cells in their dividing phase at the primary or secondary site. However, during the floating condition, cancer cells halt their multiplication process and proceed through the various steps of metastasis. Current study showed that a novel CDK inhibitor 4ab induced autophagy and endoplasmic reticulum (ER) stress in agressive cancer cells grown under adherent and floating conditions resulting in paraptosis. Further, our results showed that 4ab efficiently induced cell death in aggressive cancer cells through ER stress-mediated activation of JNK signaling. Additionally, was observed that treatment of 4ab in tumor-bearing mice displayed a significant reduction in tumor burden and micro-metastasis. The outcome of these studies showed that 4ab can be a potential anti-tumor and anti-metastatic agent.

Graphical abstract

Graphical representation of 4ab: image representing the effect of 4ab on death-inducing pathways in aggressive cancer cells. 4ab induces ER stress and activates autophagy leading to vacuolation of there by causing apoptosis in aggressive cancer cells.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We would also like to thank our lab colleagues, particularly Abubakar Wani (St. Jude Children Hospital, USA), Shariqa Aisha (CSIR IIIM, India) for their fruitful discussions, proof read  and valuable inputs. We would like to thank CSIR-IIIM for providing publication approval (Institutional Publication ID No. CSIR-IIIM/IPR/00465).

Funding

Funding for F.M. laboratory was provided by the Council of Scientific and Industrial Research (CSIR) India fellowship, a grant from the Department of Biotechnology, Ministry of Science of Technology (DBT) (BT/IN/SWISS/48/FM/2018-19). CSIR-SRF budget head for providing fellowship to S.K.

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  1. Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Sanat Nagar, Srinagar, Jammu and Kashmir, 190005, India

    Sameer Ullah Khan, Kaneez Fatima & Fayaz Malik

  2. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India

    Sameer Ullah Khan & Kaneez Fatima

  3. Medicinal Chemistry CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India

    Umed Singh & Parvinder Paul Singh

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Contributions

FM supervised the study; FM and SK designed the experiments; SK performed most of the experiments and wrote the paper; SK and KF helped in the interpretation of the results; SK and KF repeated most of the experiments; SK draws the graphical abstract; SK and KF performed animal experimentation. US and PP synthesized the molecule.

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The use of experimental animals in this study was approved by the Ethics and Institutional Animal Care and Use, Committees of the Council of Scientific and Industrial Research-Indian Institute of Integrative Medicine (CSIR-IIIM) following guidelines of the Committee for the Purpose of Control and Supervision of Experiment on Animals (CPCSEA). I confirm that all methods were carried out in accordance with relevant guidelines and regulations. I confirm that the study was carried out in compliance with the ARRIVE guidelines.

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Khan, S.U., Fatima, K., Singh, U. et al. Small molecule ‘4ab’ induced autophagy and endoplasmic reticulum stress-mediated death of aggressive cancer cells grown under adherent and floating conditions. Med Oncol 40, 121 (2023). https://doi.org/10.1007/s12032-023-01963-5

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