Abstract
Adult T cell leukemia/lymphoma (ATL) is an aggressive malignant T cell disease caused by human T cell leukemia virus-I (HTLV-1). Treatment outcomes for aggressive subtypes of ATL remain poor, with little improvement in overall survival since HTLV-1 was discovered. Therefore, new therapeutic strategies for ATL are required. STF-62247 induces autophagy and selectively kills renal cell carcinoma without apoptotic cell death. Here, we demonstrate that STF-62247 reduced cell viability and resulted in autophagosome accumulation and autophagy in leukemic cell lines (S1T, MT-2, and Jurkat). Interestingly, STF-62247 induced apoptosis in HTLV-1-infected cell lines (S1T and MT-2), as indicated by DNA fragmentation and caspase activation, but not in non-HTLV-1-infected Jurkat cells; a caspase inhibitor did not prevent this caspase-associated cell death. STF-62247 also increased nuclear endonuclease G levels. Furthermore, STF-62247 reduced cell viability and increased the number of apoptotic cells in peripheral blood mononuclear cells collected from patients with acute ATL, which has a poor prognosis. Therefore, STF-62247 may have novel therapeutic potential for ATL. This is the first evidence to demonstrate the cell growth-inhibitory effect of an autophagy inducer by caspase-dependent apoptosis and caspase-independent cell death via autophagy and endonuclease G in leukemic cells.
Highlights
Adult T cell leukemia/lymphoma (ATL), a malignancy of peripheral CD4+ T cells caused by human T cell leukemia virus-I (HTLV-1), is a retrovirus infecting approximately 10–15 million people worldwide, mainly in southern Japan, the Caribbean basin, South America, Melanesia, and Equatorial Africa [1,2,3]
Multiple studies have shown that genetic knockdown of autophagy-related Atg proteins or pharmacological inhibition of autophagy can effectively enhance tumor cell death induced by a diverse array of anticancer drugs in preclinical models [15]
Autophagy levels increased in the presence of STF-62247 in cells pre-treated with bafilomycin A1, a specific inhibitor of vacuolar proton ATPase (Figure 2C, 2D)
Summary
Adult T cell leukemia/lymphoma (ATL), a malignancy of peripheral CD4+ T cells caused by human T cell leukemia virus-I (HTLV-1), is a retrovirus infecting approximately 10–15 million people worldwide, mainly in southern Japan, the Caribbean basin, South America, Melanesia, and Equatorial Africa [1,2,3]. Intensive multiagent chemotherapies with or without subsequent allogeneic hematopoietic stem cell transplantation are usually recommended for acute, www.oncotarget.com lymphoma, or unfavorable chronic subtypes (aggressive ATL) [5, 6]. Autophagy can be activated in response to multiple stresses and has been demonstrated to promote tumor cell survival and drug resistance [9]. It can be tumor suppressive through the elimination of oncogenic protein substrates, damaged organelles, and toxic unfolded proteins [10]. Deregulation of autophagy occurs in multiple types of cancer, with current research supporting a complex and cellular context-specific role for this process during oncogenic transformation. The autophagy inducer STF-62247 was identified as selectively toxic and growth inhibitory to renal cell carcinoma lacking Von Hippel-Lindau (VHL) tumor suppressor activity, an effect that occurred without apoptosis [12]
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