Putative tumor suppressor Lats2 induces apoptosis through downregulation of Bcl-2 and Bcl-xL

Hengning Ke; Jing Pei; Zhenya Ni; Hong Xia; Huilin Qi; Tishonna Woods; Ameeta Kelekar; Wufan Tao

doi:10.1016/j.yexcr.2004.04.031

Putative tumor suppressor Lats2 induces apoptosis through downregulation of Bcl-2 and Bcl-x_L

Hengning Ke, Jing Pei, Zhenya Ni, Hong Xia, Huilin Qi, Tishonna Woods, Ameeta Kelekar, Wufan Tao

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

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Abstract

Lats2, also known as Kpm, is the second mammalian member of the novel Lats tumor suppressor gene family. Recent studies have demonstrated that Lats2 negatively regulates the cell cycle by controlling G1/S and/or G2/M transition. To further understand the role of Lats2 in the control of human cancer development, we have expressed the protein in human lung cancer cells by transduction of a replication-deficient adenovirus expressing human Lats2 (Ad-Lats2). Using a variety of techniques, including Annexin V uptake, cleavage of PARP, and DNA laddering, we have demonstrated that the ectopic expression of human Lats2 induced apoptosis in two lung cancer cell lines, A549 and H1299. Caspases-3, 7, 8, and 9 were processed in the Ad-Lats2-transduced cells; however, it was active caspase-9, not caspase-8, that initiated the caspase cascade. Inhibitors specific to caspase-3 and 9 delayed the onset of Lats2-mediated apoptosis. Western blot analysis revealed that anti-apoptotic proteins, BCL-2 and BCL-x_L, but not the pro-apoptotic protein, BAX, were downregulated in Ad-Lats2-transduced human lung cancer cells. Overexpression of either Bcl-2 or Bcl-x_L in these cells lead to the suppression of Lats2-mediated caspase cleavage and apoptosis. These results show that Lats2 induces apoptosis through downregulating anti-apoptotic proteins, BCL-2 and BCL-x_L, in human lung cancer cells.

Original language	English (US)
Pages (from-to)	329-338
Number of pages	10
Journal	Experimental Cell Research
Volume	298
Issue number	2
DOIs	https://doi.org/10.1016/j.yexcr.2004.04.031
State	Published - Aug 15 2004

Bibliographical note

Funding Information:
We are grateful to Dr. Catherine Verfaillie for her support and helpful advice for this research. We thank Dr. Tian Xu at Yale University for the anti-LATS2 antibody, and Dr. Robert Kratzke and David Kiang for the human lung cancer cell lines, H1299 and A549. Sandy Johnson and John D. Andersen are acknowledged for editing. We also thank Gregory Veltri and Janet Peller with their assistance for FACS and data analyses. This work is supported by a Research Scholar Grant from the American Cancer Society (RSG-02-065-01-MGO) and a Career Development Award from American Lung Association (CI-003-N) to W. Tao.

Keywords

Apoptosis
Bcl-2
Bcl-x
Caspase
Human Lats2
Putative tumor suppressor

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.yexcr.2004.04.031

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title = "Putative tumor suppressor Lats2 induces apoptosis through downregulation of Bcl-2 and Bcl-xL",

abstract = "Lats2, also known as Kpm, is the second mammalian member of the novel Lats tumor suppressor gene family. Recent studies have demonstrated that Lats2 negatively regulates the cell cycle by controlling G1/S and/or G2/M transition. To further understand the role of Lats2 in the control of human cancer development, we have expressed the protein in human lung cancer cells by transduction of a replication-deficient adenovirus expressing human Lats2 (Ad-Lats2). Using a variety of techniques, including Annexin V uptake, cleavage of PARP, and DNA laddering, we have demonstrated that the ectopic expression of human Lats2 induced apoptosis in two lung cancer cell lines, A549 and H1299. Caspases-3, 7, 8, and 9 were processed in the Ad-Lats2-transduced cells; however, it was active caspase-9, not caspase-8, that initiated the caspase cascade. Inhibitors specific to caspase-3 and 9 delayed the onset of Lats2-mediated apoptosis. Western blot analysis revealed that anti-apoptotic proteins, BCL-2 and BCL-xL, but not the pro-apoptotic protein, BAX, were downregulated in Ad-Lats2-transduced human lung cancer cells. Overexpression of either Bcl-2 or Bcl-xL in these cells lead to the suppression of Lats2-mediated caspase cleavage and apoptosis. These results show that Lats2 induces apoptosis through downregulating anti-apoptotic proteins, BCL-2 and BCL-xL, in human lung cancer cells.",

keywords = "Apoptosis, Bcl-2, Bcl-x, Caspase, Human Lats2, Putative tumor suppressor",

author = "Hengning Ke and Jing Pei and Zhenya Ni and Hong Xia and Huilin Qi and Tishonna Woods and Ameeta Kelekar and Wufan Tao",

note = "Funding Information: We are grateful to Dr. Catherine Verfaillie for her support and helpful advice for this research. We thank Dr. Tian Xu at Yale University for the anti-LATS2 antibody, and Dr. Robert Kratzke and David Kiang for the human lung cancer cell lines, H1299 and A549. Sandy Johnson and John D. Andersen are acknowledged for editing. We also thank Gregory Veltri and Janet Peller with their assistance for FACS and data analyses. This work is supported by a Research Scholar Grant from the American Cancer Society (RSG-02-065-01-MGO) and a Career Development Award from American Lung Association (CI-003-N) to W. Tao.",

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T1 - Putative tumor suppressor Lats2 induces apoptosis through downregulation of Bcl-2 and Bcl-xL

AU - Ke, Hengning

AU - Pei, Jing

AU - Ni, Zhenya

AU - Xia, Hong

AU - Qi, Huilin

AU - Woods, Tishonna

AU - Kelekar, Ameeta

AU - Tao, Wufan

N1 - Funding Information: We are grateful to Dr. Catherine Verfaillie for her support and helpful advice for this research. We thank Dr. Tian Xu at Yale University for the anti-LATS2 antibody, and Dr. Robert Kratzke and David Kiang for the human lung cancer cell lines, H1299 and A549. Sandy Johnson and John D. Andersen are acknowledged for editing. We also thank Gregory Veltri and Janet Peller with their assistance for FACS and data analyses. This work is supported by a Research Scholar Grant from the American Cancer Society (RSG-02-065-01-MGO) and a Career Development Award from American Lung Association (CI-003-N) to W. Tao.

PY - 2004/8/15

Y1 - 2004/8/15

N2 - Lats2, also known as Kpm, is the second mammalian member of the novel Lats tumor suppressor gene family. Recent studies have demonstrated that Lats2 negatively regulates the cell cycle by controlling G1/S and/or G2/M transition. To further understand the role of Lats2 in the control of human cancer development, we have expressed the protein in human lung cancer cells by transduction of a replication-deficient adenovirus expressing human Lats2 (Ad-Lats2). Using a variety of techniques, including Annexin V uptake, cleavage of PARP, and DNA laddering, we have demonstrated that the ectopic expression of human Lats2 induced apoptosis in two lung cancer cell lines, A549 and H1299. Caspases-3, 7, 8, and 9 were processed in the Ad-Lats2-transduced cells; however, it was active caspase-9, not caspase-8, that initiated the caspase cascade. Inhibitors specific to caspase-3 and 9 delayed the onset of Lats2-mediated apoptosis. Western blot analysis revealed that anti-apoptotic proteins, BCL-2 and BCL-xL, but not the pro-apoptotic protein, BAX, were downregulated in Ad-Lats2-transduced human lung cancer cells. Overexpression of either Bcl-2 or Bcl-xL in these cells lead to the suppression of Lats2-mediated caspase cleavage and apoptosis. These results show that Lats2 induces apoptosis through downregulating anti-apoptotic proteins, BCL-2 and BCL-xL, in human lung cancer cells.

AB - Lats2, also known as Kpm, is the second mammalian member of the novel Lats tumor suppressor gene family. Recent studies have demonstrated that Lats2 negatively regulates the cell cycle by controlling G1/S and/or G2/M transition. To further understand the role of Lats2 in the control of human cancer development, we have expressed the protein in human lung cancer cells by transduction of a replication-deficient adenovirus expressing human Lats2 (Ad-Lats2). Using a variety of techniques, including Annexin V uptake, cleavage of PARP, and DNA laddering, we have demonstrated that the ectopic expression of human Lats2 induced apoptosis in two lung cancer cell lines, A549 and H1299. Caspases-3, 7, 8, and 9 were processed in the Ad-Lats2-transduced cells; however, it was active caspase-9, not caspase-8, that initiated the caspase cascade. Inhibitors specific to caspase-3 and 9 delayed the onset of Lats2-mediated apoptosis. Western blot analysis revealed that anti-apoptotic proteins, BCL-2 and BCL-xL, but not the pro-apoptotic protein, BAX, were downregulated in Ad-Lats2-transduced human lung cancer cells. Overexpression of either Bcl-2 or Bcl-xL in these cells lead to the suppression of Lats2-mediated caspase cleavage and apoptosis. These results show that Lats2 induces apoptosis through downregulating anti-apoptotic proteins, BCL-2 and BCL-xL, in human lung cancer cells.

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KW - Putative tumor suppressor

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