The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells

Abstract

The role of autophagy in oncogenesis remains ambiguous, and mechanisms that induce autophagy and regulate its outcome in human cancers are poorly understood. The maternally imprinted Ras-related tumor suppressor gene aplasia Ras homolog member I (ARHI; also known as DIRAS3) is downregulated in more than 60% of ovarian cancers, and here we show that re-expression of ARHI in multiple human ovarian cancer cell lines induces autophagy by blocking PI3K signaling and inhibiting mammalian target of rapamycin (mTOR), upregulating ATG4, and colocalizing with cleaved microtubule-associated protein light chain 3 (LC3) in autophagosomes. Furthermore, ARHI is required for spontaneous and rapamycin-induced autophagy in normal and malignant cells. Although ARHI re-expression led to autophagic cell death when SKOv3 ovarian cancer cells were grown in culture, it enabled the cells to remain dormant when they were grown in mice as xenografts. When ARHI levels were reduced in dormant cells, xenografts grew rapidly. However, inhibition of ARHI-induced autophagy with chloroquine dramatically reduced regrowth of xenografted tumors upon reduction of ARHI levels, suggesting that autophagy contributed to the survival of dormant cells. Further analysis revealed that autophagic cell death was reduced when cultured human ovarian cancer cells in which ARHI had been re-expressed were treated with growth factors (IGF-1, M-CSF), angiogenic factors (VEGF, IL-8), and matrix proteins found in xenografts. Thus, ARHI can induce autophagic cell death, but can also promote tumor dormancy in the presence of factors that promote survival in the cancer microenvironment.

Autophagy, senescence and tumor dormancy in cancer therapy

“…3,[9][10][11][12] Finally, a recent report presents evidence for apoptosis that is dependent on prior autophagy. The transient arrest and renewed tumor growth that has been interpreted as tumor dormancy by Lu et al 2 is also a common observation in other xenograft models treated with chemotherapy or radiation; 19,20 our own studies in cell culture [21][22][23] also support the concept of drug and radiation induced senescence in tumor cells that is succeeded by proliferative recovery. We believe that this profile of response in tissue culture as well as xenograft models could prove to be a corollary of tumor dormancy and disease recurrence in the patient.…”

Association and dissociation of autophagy, apoptosis and necrosis by systematic chemical study

“…For example, autophagy is often observed in the hypoxic core of tumors where it promotes survival (Degenhardt et al, 2006), and hypoxia-inducible factor-1a is a positive regulator of autophagy (Bellot et al, 2009). Autophagy is also crucial for the survival of dormant cells in an ovarian cancer model (Lu et al, 2008). High levels of autophagy can also be observed in tumor cells following anticancer treatments.…”

Tumor Blood Vessels and Vasculogenic Mimicry – Current Knowledge and Searching for New Cellular/Molecular Targets of Anti-Angiogenic Therapy

“…An increase of VM density is connected with the increase of PGCCs amount. [10,57,92] mechanism of formation independent of VEGF, EMT contribution [52,54,57,81] interaction with ECM increase of MMPs activity and ECM remodeling [50,60] phenotype/ cell plasticity expression of stem cell multipotent phenotype (Sox-2, TWIST-1, CD133/CD44) with ability to ECs differentiation at the same time [46,68,74,84,85] tumor invasiveness and metastasis high tumor progresion and aggressiveness [50,63] prognosis for patient adverse prognostic factor, shorter survival of patient [8,50,51] Final classification of vessel-like structures needs usually more studies towards amplification of EGFR gene, which is often observed in tumor cells derived from epithelial tissue [26].…”

“…In this way, autophagy shows the action promoting tumor metastasis [78]. From the studies on ovarian cancer xenografts, it is found that ARH1 overexpression promotes cell dormancy, which is correlated with higher level of autophagosome formation [54]. The resistance of breast cancer cells to TRAIL-dependent apoptosis is induced by autophagy as a result of death receptor expression decrease [21].…”