SHetA2 Attack on Mortalin and Colleagues in Cancer Therapy and Prevention

Abstract

Heat Shock Proteins of the 70-kDa family (HSP70s) do not cause cancer by themselves, but instead protect cells as they transform into cancer. These molecular chaperones bind numerous client proteins and utilize ATP hydrolysis to facilitate proper protein folding, formation of functional complexes and cellular localizations, or degradation of irreparably damaged proteins. Their transient upregulation by stressful situations avoids induction of programmed cell death. Continued upregulation of the mortalin, heat shock cognate (hsc70) and glucose regulated protein 78 (Grp78) support cancer development and progression by supporting pro-proliferative and metabolic functions and repressing pro-death functions of oncoproteins and tumor suppressor proteins. This review describes the discovery and development of a lead anti-cancer compound, sulfur heteroarotinoid A2 (SHetA2, NSC726189), which was originally developed to bind retinoic acid receptors, but was subsequently found to work independently of these receptors. The discovery and validation of mortalin, hsc70 and Grp78 as SHetA2 target proteins is summarized. The documented and hypothesized roles of these HSP70 proteins and their clients in the mechanism of SHetA2 inhibition of cancer without toxicity are discussed. Use of this mechanistic data to evaluate drug action in a cancer clinical trial and develop synergistic drug combinations is explained. Knowledge needed to optimize SHetA2 analogs for use in cancer therapy and prevention is proposed as future directions.

Distinct mechanism of cervical cancer cell death caused by the investigational new drug SHetA2

“…SHetA2 induced caspase-dependent apoptosis in ovarian, kidney, and lung cancer cells ( 23 – 26 ). As expected and consistent with our previous SiHa xenograft study ( 6 ), SHetA2 significantly induced caspase-3 activity in cervical cancer cell lines ( Figure 6A ). Inhibition of caspase activity with a pan-caspase inhibitor, as confirmed by caspase-3 assay ( Figure 6A ), did not significantly alter SHetA2 cytotoxicity, suggesting that SHetA2 works independently of caspase activity in cervical cancer cell lines ( Figure 6B ).…”

“…We next determined if these mitochondrial effects are also caused by SHetA2 treatment in an animal model. Previously, we demonstrated that oral administration of 60 mg/kg SHetA2 significantly inhibited the growth of SiHa cervical cancer xenografts without inducing toxicity ( 6 ). In this study, two oral doses (30 and 60 mg/kg/day) of SHetA2 induced a dose-responsive reduction in Ca Ski xenograft tumor growth ( Figure 9A ).…”

“…SHetA2 has been shown to bind three related HSP70 proteins, mortalin, Grp78 and hsc70 ( 16 ). While the role of mortalin in the mechanism of SHetA2 has been extensively studied ( 6 ), this is the first study to evaluate SHetA2 effects on hsc70. The observation that SHetA2 disrupts hsc70/AIF complexes suggests that, in addition to SHetA2 disruption of mortalin complexes, its disruption of hsc70 and potentially Grp78 complexes could contribute to the mechanism of SHetA2 cytotoxicity.…”

“…The 70 Kd family of HSPs (HSP70s) consists of 14 members, which each have unique and redundant functions throughout the cell ( 5 ). The mortalin member of this family is localized throughout the cells, but it’s primary location and function are in maintaining mitochondrial health ( 5 , 6 ). Increased levels of mortalin promote carcinogenesis and cancer progression by supporting overactive mitochondria and sequestering p53 in the cytoplasm away from the mitochondria and nucleus where it can initiate apoptosis ( 7 – 10 ).…”

Identification of a new member of Mortaparib class of inhibitors that target mortalin and PARP1

“…Besides its essential role in maintaining the mitochondrial integrity ( Czarnecka et al, 2006 ; Havalova et al, 2021 ), mortalin has been shown to interact with several proteins and modulate their functions in control of cell division and migration ( Wadhwa et al, 1998 ; Mizukoshi et al, 1999 ; Sacht et al, 1999 ; Takano et al, 2001 ; Schwarzer et al, 2002 ; Wadhwa et al, 2003 ; Chen et al, 2014 ). It has been demonstrated to interact with the key tumor suppressor protein p53, functionally inactivated in a large majority of cancers ( Wadhwa et al, 1998 ; Benbrook et al, 2014 ; Sane et al, 2014 ; Pham et al, 2019 ; Benbrook, 2022 ). The interaction of mortalin and p53 in the cytoplasm results in cytoplasmic retention and hence the inactivation of transcriptional activation function of p53 in cancer cells ( Wadhwa et al, 1998 ; Kaul et al, 2001 ; Wadhwa et al, 2002c ; Walker et al, 2006 ).…”