Sensitization of cancer cells towards Cisplatin and Carboplatin by protein kinase D inhibitors through modulation of ATP7A/B (copper transport ATPases)

Janardhanan, Prajit; Somasundaran, Aswathi Kodenchery; Balakrishnan, Anjali Jayasree; Pilankatta, Rajendra

doi:10.1016/j.ctarc.2022.100613

Cited by 8 publications

(11 citation statements)

References 34 publications

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“…The efficacy of CDDP and other platinum‐based drugs against malignant tumors depends on the drug resistance of cancer cells, but the exact mechanism is still unknown. ATP7A and ATP7B are known to induce drug resistance to CDDP 16,57 . Both ATP7A and ATP7B are membrane‐bound molecular pumps belonging to P‐type ATPases and are involved in copper homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Novel mechanism of cisplatin resistance in head and neck squamous cell carcinoma involving extracellular vesicles and a copper transporter system

Ogawa,

Ono,

Ryumon

et al. 2024

Head & Neck

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BackgroundCisplatin (CDDP) plays a central role in chemotherapy for head and neck squamous cell carcinoma (HNSCC), but drug resistance in HNSCC chemotherapy remains a problem, and the mechanism of CDDP resistance is unclear. We investigated CDDP‐resistance mechanisms mediated by extracellular vesicles (EVs) and ATPase copper transporting beta (ATP7B) in HNSCC.MethodsWe established CDDP‐resistant sublines of HNSCC cells and verified their ATP7B expression. We used an EV secretion inhibitor (GW4869) and ATP7B short hairpin (sh)RNA transfection to examine the correlation between EV secretion and ATP7B expression.ResultsThe CDDP‐resistant HNSCC sublines showed decreased CDDP sensitivity and increased ATP7B expression. GW4869 suppressed ATP7B expression, and ATP7B shRNA transfection suppressed EV secretion. The suppressions of EV secretion and ATP7B expression both enhanced CDDP's cell‐killing effect.ConclusionsEVs were involved in the ATP7B‐mediated mechanism underlying CDDP resistance. Further clarification of the EV‐induced CDDP‐resistance mechanism may lead to novel therapeutic strategies for HNSCC.

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Section: Discussionmentioning

confidence: 99%

Novel mechanism of cisplatin resistance in head and neck squamous cell carcinoma involving extracellular vesicles and a copper transporter system

Ogawa,

Ono,

Ryumon

et al. 2024

Head & Neck

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“…This PKD inhibitor increased proteasome-mediated degradation of ATPase coppertransporting α/β (ATP7A/B) by blocking phosphorylation. 57 Since the selectivity of CID2011756 is unknown, it remains to be determined if and how much inhibition of PKD1−3 accounts for its synergistic effects. It should be noted that the combined inhibition of PKD is not always desirable, and there is evidence that activating it could also be beneficial, such as the case of suramin (a PKD activator) and a DNA methyltransferase inhibitor combination for breast cancer treatment, where a role of PKD1 in tumor suppression is implicated.…”

Section: Selectivitymentioning

confidence: 99%

“…Previous studies have mainly focused on their use in combination therapy for cancer, and the outcomes have been mixed. PKD inhibitors have been shown to synergize with several chemotherapeutics, including paclitaxel and cisplatin, as well as targeted agents such as the multikinase inhibitor regorafenib . Specifically, inhibition of PKD by CRT0066101 significantly enhanced the cytotoxic effect of regorafenib in multiple colon cancer cell lines by synergistically inducing apoptosis and downregulating ERK, AKT, and NF-κB signaling .…”

Section: Introductionmentioning

confidence: 99%

“…Another PKD inhibitor, CID2011756, enhanced the sensitivity of cancer cells to cisplatin or carboplatin. This PKD inhibitor increased proteasome-mediated degradation of ATPase copper-transporting α/β (ATP7A/B) by blocking phosphorylation . Since the selectivity of CID2011756 is unknown, it remains to be determined if and how much inhibition of PKD1–3 accounts for its synergistic effects.…”

Section: Introductionmentioning

confidence: 99%

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Small Molecule Inhibitors of Protein Kinase D: Early Development, Current Approaches, and Future Directions

Wang

Wipf

2022

J. Med. Chem.

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Now entering its fourth decade, research on the biological function, small molecule inhibition, and disease relevance of the three known isoforms of protein kinase D, PKD1, PKD2, and PKD3, has entered a mature development stage. This miniperspective focuses on the medicinal chemistry that provided a structurally diverse set of mainly active site inhibitors, which, for a brief time period, moved through preclinical development stages but have yet to be tested in clinical trials. In particular, between 2006 and 2012, a rapid expansion of synthetic efforts led to several moderately to highly PKD-selective chemotypes but did not yet achieve PKD subtype selectivity or resolve general toxicity and pharmacokinetic challenges. In addition to cancer, other unresolved medical needs in cardiovascular, inflammatory, and metabolic diseases would, however, benefit from a renewed focus on potent and selective PKD modulators.

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“…Studies have shown that breast cancer patients with poor prognoses exhibit higher expression of the copper importer solute carrier family 31 member 1 (SLC31A1) and the copper binding protein ceruloplasmin, which could be utilized as potential prognosis factors ( 10 – 12 ). Decreased expression of the copper exporters ATPase copper transporting α (ATP7A) and ATPase copper transporting β (ATP7B) have been associated with decreased chemotherapy resistance in breast cancer cells ( 13 , 14 ). It is currently not fully understood how copper metabolism may be involved in breast cancer or the potential mechanisms by which it may influence the development or progression of the disease.…”

Section: Introductionmentioning

confidence: 99%

Copper-related genes predict prognosis and characteristics of breast cancer

2023

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BackgroundThe role of copper in cancer treatment is multifaceted, with copper homeostasis-related genes associated with both breast cancer prognosis and chemotherapy resistance. Interestingly, both elimination and overload of copper have been reported to have therapeutic potential in cancer treatment. Despite these findings, the exact relationship between copper homeostasis and cancer development remains unclear, and further investigation is needed to clarify this complexity.MethodsThe pan-cancer gene expression and immune infiltration analysis were performed using the Cancer Genome Atlas Program (TCGA) dataset. The R software packages were employed to analyze the expression and mutation status of breast cancer samples. After constructing a prognosis model to separate breast cancer samples by LASSO-Cox regression, we examined the immune statement, survival status, drug sensitivity and metabolic characteristics of the high- and low-copper related genes scoring groups. We also studied the expression of the constructed genes using the human protein atlas database and analyzed their related pathways. Finally, copper staining was performed with the clinical sample to investigate the distribution of copper in breast cancer tissue and paracancerous tissue.ResultsPan-cancer analysis showed that copper-related genes are associated with breast cancer, and the immune infiltration profile of breast cancer samples is significantly different from that of other cancers. The essential copper-related genes of LASSO-Cox regression were ATP7B (ATPase Copper Transporting Beta) and DLAT (Dihydrolipoamide S-Acetyltransferase), whose associated genes were enriched in the cell cycle pathway. The low-copper related genes scoring group presented higher levels of immune activation, better probabilities of survival, enrichment in pathways related to pyruvate metabolism and apoptosis, and higher sensitivity to chemotherapy drugs. Immunohistochemistry staining showed high protein expression of ATP7B and DLAT in breast cancer samples. The copper staining showed copper distribution in breast cancer tissue.ConclusionThis study displayed the potential impacts of copper-related genes on the overall survival, immune infiltration, drug sensitivity and metabolic profile of breast cancer, which could predict patients’ survival and tumor statement. These findings may serve to support future research efforts aiming at improving the management of breast cancer.

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Sensitization of cancer cells towards Cisplatin and Carboplatin by protein kinase D inhibitors through modulation of ATP7A/B (copper transport ATPases)

Cited by 8 publications

References 34 publications

Novel mechanism of cisplatin resistance in head and neck squamous cell carcinoma involving extracellular vesicles and a copper transporter system

Novel mechanism of cisplatin resistance in head and neck squamous cell carcinoma involving extracellular vesicles and a copper transporter system

Small Molecule Inhibitors of Protein Kinase D: Early Development, Current Approaches, and Future Directions

Copper-related genes predict prognosis and characteristics of breast cancer

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