The prospect of serum and glucocorticoid-inducible kinase 1 (SGK1) in cancer therapy: a rising star

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Abstract

Serum and glucocorticoid-inducible kinase 1 (SGK1) is an AGC kinase that has been reported to be involved in a variety of physiological and pathological processes. Recent evidence has accumulated that SGK1 acts as an essential Akt-independent mediator of phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway in cancer. SGK1 is overexpressed in several tumors, including prostate cancer, colorectal carcinoma, glioblastoma, breast cancer, and endometrial cancer. The functions of SGK1 include regulating tumor growth, survival, metastasis, autophagy, immunoregulation, calcium (Ca ²⁺) signaling, cancer stem cells, cell cycle, and therapeutic resistance. In this review, we introduce the pleiotropic role of SGK1 in the development and progression of tumors, summarize its downstream targets, and integrate the knowledge provided by preclinical studies that the prospect of SGK1 inhibition as a potential therapeutic approach.

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Regulatory T cells in cancer immunotherapy

Atsushi Tanaka, Shimon Sakaguchi (2017)

FOXP3-expressing regulatory T (Treg) cells, which suppress aberrant immune response against self-antigens, also suppress anti-tumor immune response. Infiltration of a large number of Treg cells into tumor tissues is often associated with poor prognosis. There is accumulating evidence that the removal of Treg cells is able to evoke and enhance anti-tumor immune response. However, systemic depletion of Treg cells may concurrently elicit deleterious autoimmunity. One strategy for evoking effective tumor immunity without autoimmunity is to specifically target terminally differentiated effector Treg cells rather than all FOXP3+ T cells, because effector Treg cells are the predominant cell type in tumor tissues. Various cell surface molecules, including chemokine receptors such as CCR4, that are specifically expressed by effector Treg cells can be the candidates for depleting effector Treg cells by specific cell-depleting monoclonal antibodies. In addition, other immunological characteristics of effector Treg cells, such as their high expression of CTLA-4, active proliferation, and apoptosis-prone tendency, can be exploited to control specifically their functions. For example, anti-CTLA-4 antibody may kill effector Treg cells or attenuate their suppressive activity. It is hoped that combination of Treg-cell targeting (e.g., by reducing Treg cells or attenuating their suppressive activity in tumor tissues) with the activation of tumor-specific effector T cells (e.g., by cancer vaccine or immune checkpoint blockade) will make the current cancer immunotherapy more effective.

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Store-operated calcium channels.

Anant B. Parekh, James W. Putney (2005)

In electrically nonexcitable cells, Ca(2+) influx is essential for regulating a host of kinetically distinct processes involving exocytosis, enzyme control, gene regulation, cell growth and proliferation, and apoptosis. The major Ca(2+) entry pathway in these cells is the store-operated one, in which the emptying of intracellular Ca(2+) stores activates Ca(2+) influx (store-operated Ca(2+) entry, or capacitative Ca(2+) entry). Several biophysically distinct store-operated currents have been reported, but the best characterized is the Ca(2+) release-activated Ca(2+) current, I(CRAC). Although it was initially considered to function only in nonexcitable cells, growing evidence now points towards a central role for I(CRAC)-like currents in excitable cells too. In spite of intense research, the signal that relays the store Ca(2+) content to CRAC channels in the plasma membrane, as well as the molecular identity of the Ca(2+) sensor within the stores, remains elusive. Resolution of these issues would be greatly helped by the identification of the CRAC channel gene. In some systems, evidence suggests that store-operated channels might be related to TRP homologs, although no consensus has yet been reached. Better understood are mechanisms that inactivate store-operated entry and hence control the overall duration of Ca(2+) entry. Recent work has revealed a central role for mitochondria in the regulation of I(CRAC), and this is particularly prominent under physiological conditions. I(CRAC) therefore represents a dynamic interplay between endoplasmic reticulum, mitochondria, and plasma membrane. In this review, we describe the key electrophysiological features of I(CRAC) and other store-operated Ca(2+) currents and how they are regulated, and we consider recent advances that have shed insight into the molecular mechanisms involved in this ubiquitous and vital Ca(2+) entry pathway.

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Calcium in tumour metastasis: new roles for known actors.

Natalia Prevarskaya, Roman Skryma, Yaroslav M Shuba (2011)

In most cases, metastasis, not the primary tumour per se, is the main cause of mortality in cancer patients. In order to effectively escape the tumour, enter the circulation and establish secondary growth in distant organs cancer cells must develop an enhanced propensity to migrate. The ubiquitous second messenger Ca²⁺ is a crucial regulator of cell migration. Recently, a number of known molecular players in cellular Ca²⁺ homeostasis, including calcium release-activated calcium channel protein 1 (ORAI1), stromal interaction molecule 1 (STIM1) and transient receptor potential (TRP) channels, have been implicated in tumour cell migration and the metastatic cell phenotype. We discuss how these developments have increased our understanding of the Ca²⁺ dependence of pro-metastatic behaviours.

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Author and article information

Contributors

Ruizhe Zhu

Gang Yang

Zhe Cao

Kexin Shen

Lianfang Zheng

Jianchun Xiao

Lei You

Taiping Zhang

Journal

Journal ID (nlm-ta): Ther Adv Med Oncol

Journal ID (iso-abbrev): Ther Adv Med Oncol

Journal ID (publisher-id): TAM

Journal ID (hwp): sptam

Title: Therapeutic Advances in Medical Oncology

Publisher: SAGE Publications (Sage UK: London, England )

ISSN (Print): 1758-8340

ISSN (Electronic): 1758-8359

Publication date (Electronic): 15 July 2020

Publication date Collection: 2020

Volume: 12

Electronic Location Identifier: 1758835920940946

Affiliations

[1-1758835920940946]Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

[2-1758835920940946]Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

[3-1758835920940946]Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

[4-1758835920940946]Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

[5-1758835920940946]Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

[6-1758835920940946]Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

[7-1758835920940946]Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

[8-1758835920940946]Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing 100730, China

Author notes

[*] tpingzhang@ 123456yahoo.com

[*]

These authors contributed equally.

Article

Publisher ID: 10.1177_1758835920940946

DOI: 10.1177/1758835920940946

PMC ID: 7364809

PubMed ID: 32728395

SO-VID: b6ad8817-774e-476b-b87e-9df3704c58cb

License:

This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

History

Date received : 2 March 2020

Date accepted : 16 June 2020

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cover-date January-December 2020

typesetter ts1

Keywords: autophagy,calcium signaling,chemoresistance,immunoregulation,pi3k signaling,sgk1,therapeutic target

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Keywords: autophagy, calcium signaling, chemoresistance, immunoregulation, pi3k signaling, sgk1, therapeutic target

The prospect of serum and glucocorticoid-inducible kinase 1 (SGK1) in cancer therapy: a rising star

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Measurement of Glucocorticoid Receptor Signaling in Major Depression

Most cited references 97

Regulatory T cells in cancer immunotherapy

Store-operated calcium channels.

Calcium in tumour metastasis: new roles for known actors.

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