Small molecule binds with lymphocyte antigen 6k to induce cancer cell death

Senyi Benti; Purushottam B. Tiwari; Dustin W. Goodlett; Leily Daneshian; Grant B. Kern; Mark D. Smith; Aykut Uren; Maksymilian Chruszcz; Linda S. Shimizu; Geeta Upadhyay

doi:10.3390/cancers12020509

Small molecule binds with lymphocyte antigen 6k to induce cancer cell death

Senyi Benti
, Purushottam B. Tiwari
, Dustin W. Goodlett
, Leily Daneshian
, Grant B. Kern
, Mark D. Smith
, Aykut Uren
, Maksymilian Chruszcz
, Linda S. Shimizu
, Geeta Upadhyay

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

Elevated gene expression of Lymphocyte antigen 6K (LY6K) in cancer cells is associated with poor survival outcomes in multiple different cancer types including cervical, breast, ovarian, lung, and head and neck cancer. Since inhibition of LY6K expression inhibits cancer cell growth, we set out to explore whether pharmacological inhibition of LY6K could produce the same effect. We screened small molecule libraries for direct binding to recombinant LY6K protein in a surface plasmon resonance assay. We found that NSC243928 directly binds to the full-length and mature forms of LY6K and inhibits growth of HeLa cells that express LY6K. NSC243928 did not display binding with LY6D or LY6E. Our data demonstrate a first-time proof of principle study that pharmacological inhibition of LY6K using small molecules in cancer cells is a valid approach to developing targeted therapies against LY6K. This approach will be specifically relevant in hard-to-treat cancers where LY6K is highly expressed, such as cervical, pancreatic, ovarian, head and neck, lung, gastric, and triple-negative breast cancers.

Original language	English
Article number	509
Journal	Cancers
Volume	12
Issue number	2
DOIs	https://doi.org/10.3390/cancers12020509
State	Published - Feb 2020
Externally published	Yes

Funding

Funding: This research has been supported by NIH R01CA227694 and Uniformed Services University Start-Up funds by Vice President of Research office, USUHS to Geeta Upadhyay. NIH R01CA227694 sub-award to Linda Shimizu and Maksymilian Chruszcz. Part of the study was supported by Institutional American Cancer Society Grant to Mike Atkins, Georgetown University, sub-award to Geeta Upadhyay at her work at Georgetown University. The experimental SPR sensorgrams were measured using a Biacore T200 instrument and were evaluated using the Biacore T200 evaluation software version 1.0 available in the Biacore Molecular Interaction Shared Resource (BMISR) facility at Georgetown University. The BMISR is supported by NIH grant P30CA51008. This research has been supported by NIH R01CA227694 and Uniformed Services University Start-Up funds by Vice President of Research office, USUHS to Geeta Upadhyay. NIH R01CA227694 sub-award to Linda Shimizu and Maksymilian Chruszcz. Part of the study was supported by Institutional American Cancer Society Grant to Mike Atkins, Georgetown University, sub-award to Geeta Upadhyay at her work at Georgetown University. The experimental SPR sensorgrams were measured using a Biacore T200 instrument and were evaluated using the Biacore T200 evaluation software version 1.0 available in the Biacore Molecular Interaction Shared Resource (BMISR) facility at Georgetown University. The BMISR is supported by NIH grant P30CA51008.

Keywords

Cervical cancer
LY6K
NSC243928
Small molecule
Surface plasmon resonance

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10.3390/cancers12020509

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title = "Small molecule binds with lymphocyte antigen 6k to induce cancer cell death",

abstract = "Elevated gene expression of Lymphocyte antigen 6K (LY6K) in cancer cells is associated with poor survival outcomes in multiple different cancer types including cervical, breast, ovarian, lung, and head and neck cancer. Since inhibition of LY6K expression inhibits cancer cell growth, we set out to explore whether pharmacological inhibition of LY6K could produce the same effect. We screened small molecule libraries for direct binding to recombinant LY6K protein in a surface plasmon resonance assay. We found that NSC243928 directly binds to the full-length and mature forms of LY6K and inhibits growth of HeLa cells that express LY6K. NSC243928 did not display binding with LY6D or LY6E. Our data demonstrate a first-time proof of principle study that pharmacological inhibition of LY6K using small molecules in cancer cells is a valid approach to developing targeted therapies against LY6K. This approach will be specifically relevant in hard-to-treat cancers where LY6K is highly expressed, such as cervical, pancreatic, ovarian, head and neck, lung, gastric, and triple-negative breast cancers.",

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author = "Senyi Benti and Tiwari, \{Purushottam B.\} and Goodlett, \{Dustin W.\} and Leily Daneshian and Kern, \{Grant B.\} and Smith, \{Mark D.\} and Aykut Uren and Maksymilian Chruszcz and Shimizu, \{Linda S.\} and Geeta Upadhyay",

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month = feb,

doi = "10.3390/cancers12020509",

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AU - Benti, Senyi

AU - Tiwari, Purushottam B.

AU - Goodlett, Dustin W.

AU - Daneshian, Leily

AU - Kern, Grant B.

AU - Smith, Mark D.

AU - Uren, Aykut

AU - Chruszcz, Maksymilian

AU - Shimizu, Linda S.

AU - Upadhyay, Geeta

PY - 2020/2

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N2 - Elevated gene expression of Lymphocyte antigen 6K (LY6K) in cancer cells is associated with poor survival outcomes in multiple different cancer types including cervical, breast, ovarian, lung, and head and neck cancer. Since inhibition of LY6K expression inhibits cancer cell growth, we set out to explore whether pharmacological inhibition of LY6K could produce the same effect. We screened small molecule libraries for direct binding to recombinant LY6K protein in a surface plasmon resonance assay. We found that NSC243928 directly binds to the full-length and mature forms of LY6K and inhibits growth of HeLa cells that express LY6K. NSC243928 did not display binding with LY6D or LY6E. Our data demonstrate a first-time proof of principle study that pharmacological inhibition of LY6K using small molecules in cancer cells is a valid approach to developing targeted therapies against LY6K. This approach will be specifically relevant in hard-to-treat cancers where LY6K is highly expressed, such as cervical, pancreatic, ovarian, head and neck, lung, gastric, and triple-negative breast cancers.

AB - Elevated gene expression of Lymphocyte antigen 6K (LY6K) in cancer cells is associated with poor survival outcomes in multiple different cancer types including cervical, breast, ovarian, lung, and head and neck cancer. Since inhibition of LY6K expression inhibits cancer cell growth, we set out to explore whether pharmacological inhibition of LY6K could produce the same effect. We screened small molecule libraries for direct binding to recombinant LY6K protein in a surface plasmon resonance assay. We found that NSC243928 directly binds to the full-length and mature forms of LY6K and inhibits growth of HeLa cells that express LY6K. NSC243928 did not display binding with LY6D or LY6E. Our data demonstrate a first-time proof of principle study that pharmacological inhibition of LY6K using small molecules in cancer cells is a valid approach to developing targeted therapies against LY6K. This approach will be specifically relevant in hard-to-treat cancers where LY6K is highly expressed, such as cervical, pancreatic, ovarian, head and neck, lung, gastric, and triple-negative breast cancers.

KW - Cervical cancer

KW - LY6K

KW - NSC243928

KW - Small molecule

KW - Surface plasmon resonance

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U2 - 10.3390/cancers12020509

DO - 10.3390/cancers12020509

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VL - 12

JO - Cancers

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M1 - 509

ER -

Small molecule binds with lymphocyte antigen 6k to induce cancer cell death

Abstract

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Keywords

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