Biochemical and Biophysical Research Communications
Induction of apoptosis in hematological cancer cells by dorsomorphin correlates with BAD upregulation
Introduction
AMP-activated protein kinase (AMPK), a critical sensor of cellular energy and nutrient levels, is normally a tumor suppressor. The tumor-suppressive functions of AMPK that have been described so far include: 1) inhibition of biosynthetic kinases such as mammalian target of rapamycin (mTOR) and acetyl-CoA carboxylase (ACC) [[1], [2], [3]]; 2) anti-Warburg effect by downregulating the glycolytic pathway [4,5]; 3) stabilization of other tumor suppressor protein, such as p53 and p27Kip1 [6], Tet2 [7]; 4) blocking the immunosuppressive signal by inducing PD-L1 degradation [8]; 5) activation of Parkin to suppress the necrosis and inflammation [9]. But if, despite its best efforts, a tumor does arise, AMPK usually becomes a tumor promoter instead [[10], [11], [12], [13], [14], [15], [16], [17]]. This may occur because AMPK protects tumor cells against the stresses that arise from their rapid cell growth and division, metabolic transformation and poor blood supply [[10], [11], [12], [13], [14], [15], [16], [17]]. This helps cancer cells to survive rather than die, and thereby drives tumor progression. Thus, rather than activation, AMPK blockade may be more effective in the therapy for such “AMPK-driven” cancers.
In this study, we show that AMPK is upregulated in a variety of hematological cancers, including acute myelogenous leukemia (AML), unspecified peripheral T-cell lymphoma (PTCL-U), angioimmunoblastic T-cell lymphoma (AITL), acute adult T-cell leukemia/lymphoma (AATL), monoclonal gammopathy of undetermined significance (MGUS), and multiple myeloma (MM), and plays key roles in maintaining viability of tumor cells. Blockade of AMPK signaling by dorsomorphin markedly induces apoptosis in Jurkat, K562 cell lines as well as primary cancerous B cells. Mechanistically, dorsomorphin significantly upregulates the expression of BAD, a pro-apoptotic member of the Bcl-2 gene family involved in initiating apoptosis [18,19]. Reduction of BAD expression by RNA interference prevents apoptosis in response to AMPK inhibition. Thus, our data found BAD integrates the anti-apoptotic effects of dorsomorphin and provided novel insights into the mechanisms by which AMPK facilitates survival signaling in hematologic cancer cells.
Section snippets
Reagents
RMPI-1640 medium and fetal bovine serum (FBS) were purchased from HyClone (Logan, USA); l-glutamine from Gibco (CA, USA); Metformin HCl (S1950) and Dorsomorphin 2HCl (S7306) from Selleckchem; Annexin V-FITC/PI apoptosis detection kit from TransGen Biotech (Beijing, China); Propidium Iodide Solution (421301) from Biolegend (CA, USA); Lipofectamine 3000 (L3000015) from Invitrogen (CA, USA).
Bioinformatics analysis of AMPK expression in hematological cancers
AMPK expression (PRKAA1 mRNA) in hematological cancers was determined by analysis of Piccaluga lymphoma,
AMPK is upregulated in a variety of hematological cancers and maintains cell survival
To investigate the role of AMPK in hematological cancers, we examined its expression (PRKAA1 mRNA) by analysis of Piccaluga lymphoma, Maia/Choi/Stegmaier Leukemia and Zhan Myeloma databases, which are available through Oncomine (www.oncomine.org). As shown in Fig. 1A–D, the level of AMPK was significantly upregulated in a variety of hematological cancers, including Acute Myelogenous Leukemia (AML), Unspecified Peripheral T-Cell Lymphoma (PTCL-U), Angioimmunoblastic T-Cell Lymphoma (AITL), Acute
Discussion
Although AMPK is traditionally regarded as a tumor suppressor, recently it has been reported to be tumor-promoter in several types of cancers, including T-lineage acute lymphoblastic leukemia (T-ALL) [11], myeloid leukemias [12], multiple myeloma [22], prostate cancer [23], glioma [24] and MLL-rearranged pediatric B-acute lymphoblastic leukemia [25], strongly indicating that AMPK may switch from tumor suppressor to promoter and thereby drive tumor development [17]. In such AMPK-driven tumors,
Declaration of competing interest
The authors declare no conflict of interest.
Acknowledgments
This study was supported by The National Natural Science Foundation of China (NSFC) (81701559), Shenzhen Basic Science Research Project (JCYJ20170818155135838, JCYJ20170413153158716, JCYJ20170818164619194). The Fourth Talents Project of Guangdong Province (Office of Talents in Guangdong [2014] No.1), Special Funds for Major Science and Technology of Guangdong Province (2019B020201014), Guangdong Provincial Research Award for Thousand Talents Program Scholars, and Nanshan pilot team project (
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Equal contributors.