The role and mechanism of autophagy in sorafenib targeted cancer therapy

Yi, Heqing; Lü, Bin; Ye, Xuemei; Li, Linfa

doi:10.1016/j.critrevonc.2016.02.006

Cited by 29 publications

(20 citation statements)

References 23 publications

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“…It has been demonstrated that sorafenib triggers autophagy in different cancer contexts (12,15). In the present study, sorafenib induced autophagy in thyroid cancer cell lines and mice xenograft models.…”

Section: Discussionsupporting

confidence: 56%

“…The process of autophagy could be activated during cancer treatment by radiation (34), chemotherapy (35) or TKI drugs (12,15). The role of autophagy in cancer treatment is complex since it is a 'double-edged sword'; autophagy may promote or inhibit cell death (12,36,37). The varying roles of autophagy in cancer treatment primarily depend on different contexts and treatments (13,37,38).…”

Section: Discussionmentioning

confidence: 99%

“…In our results, sorafenib treatment or AKT/mTOR pathway suppression induced autophagy in thyroid cancer cell lines. As autophagy plays a dual role in cancer treatment, we examined the role of autophagy in sorafenib treatment of thyroid cancer (11,12). ATG5 is a key gene in the process of autophagy that can be silenced to demonstrate the role of autophagy in different treatments (6).…”

Section: Effect Of Autophagy On Sorafenib Treated Thyroid Cancer Cellmentioning

confidence: 99%

“…Autophagy is an evolutionarily conserved process in which cytoplasmic materials are delivered to lysosomes for degradation (11). The relationship between autophagy and cancer is complex due to the dual roles of autophagy in tumor progression and cancer therapy (11,12). Several studies have reported that sorafenib induced autophagy in cancer cells (13), and it has been reported that autophagy can be induced by sorafenib in a dose-and time-dependent in several hepatocellular carcinoma (HCC) cell lines (14,15).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of autophagy enhances the targeted therapeutic effect of sorafenib in thyroid cancer

et al. 2017

Oncol Rep

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The multi-target kinase inhibitor sorafenib has been approved for the treatment of patients with advanced differentiated thyroid cancer. However, different sensitivities to sorafenib have been observed, and few patients have benefited from sorafenib treatment in the long term. In the event of acquired resistance to sorafenib it is not beneficial to continue treatment in most patients. Autophagy can be induced in a variety of cancer treatments and plays an important role in cancer treatment. The role of autophagy in sorafenib treatment of thyroid cancer has not been fully demonstrated. The present study investigated whether autophagy is activated by sorafenib during the treatment of thyroid cancer, examined the underlying mechanisms, and explored potential strategies to enhance the therapeutic sensitivity of sorafenib. Chloroquine (CQ) is an autophagy inhibitor that has been reported to increase sensitivity to various cancer treatments. Thyroid cancer xenograft model mice were treated with sorafenib, CQ, or a combination of sorafenib and CQ. We observed that CQ or sorafenib treatment suppressed tumor growth, while mice treated with the combination of sorafenib and CQ displayed significantly reduced tumor growth compared with those treated with sorafenib or CQ alone. Western blotting results indicated that sorafenib concurrently inhibited the activities of the MAPK and AKT/mTOR pathways in thyroid cancer. Autophagy was activated by sorafenib in thyroid cancer, both in vitro and in vivo, which was at least in part due to suppression of the AKT/mTOR pathway. Combination treatment including CQ could inhibit the autophagic flux induced by sorafenib. Silencing the key autophagy gene ATG5 using small interfering RNA also increased the anticancer effect of sorafenib. In summary, the present study revealed that inhibition of autophagy enhances the anticancer effect of sorafenib, and the combination of CQ with sorafenib treatment represents a potential therapeutic strategy for treating advanced differentiated thyroid cancer.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Section: Effect Of Autophagy On Sorafenib Treated Thyroid Cancer Cellmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of autophagy enhances the targeted therapeutic effect of sorafenib in thyroid cancer

et al. 2017

Oncol Rep

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“…When sorafenib was combined with pemetrexed, a folate anti-metabolite that stimulates autophagy, the treatment increased the rate of autophagy and cell death in vitro and suppressed tumor growth in vivo [41] . Thus, autophagy can either enable cell survival or promote cell death [42] , and further in-depth research is necessary for clarification.…”

Section: Autophagy and Sorafenib Resistancementioning

confidence: 99%

New knowledge of the mechanisms of sorafenib resistance in liver cancer

et al. 2017

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Sorafenib is an oral multikinase inhibitor that suppresses tumor cell proliferation and angiogenesis and promotes tumor cell apoptosis. It was approved by the FDA for the treatment of advanced renal cell carcinoma in 2006, and as a unique target drug for advanced hepatocellular carcinoma (HCC) in 2007. Sorafenib can significantly extend the median survival time of patients but only by 3-5 months. Moreover, it is associated with serious adverse side effects, and drug resistance often develops. Therefore, it is of great importance to explore the mechanisms underlying sorafenib resistance and to develop individualized therapeutic strategies for coping with these problems. Recent studies have revealed that in addition to the primary resistance, several mechanisms are underlying the acquired resistance to sorafenib, such as crosstalk involving PI3K/Akt and JAK-STAT pathways, the activation of hypoxia-inducible pathways, and epithelial-mesenchymal transition. Here, we briefly describe the function of sorafenib, its clinical application, and the molecular mechanisms for drug resistance, especially for HCC patients.

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The significance of TIMD4 expression in clear cell renal cell carcinoma

Yano

Motoshima

et al. 2017

Med Mol Morphol

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T-cell immunoglobulin and mucin domain (TIMD) family genes are related to innate immune responses. TIMD4 is a receptor for phosphatidylserine and is involved in the phagocytosis of apoptotic cells by macrophages. In the present study, we found that TIMD4 is expressed on the cancer cells of patients with clear cell renal cell carcinoma (ccRCC). TIMD4 was immunostained in the resected samples of 89 patients diagnosed as ccRCC. High expression of TIMD4 in cancer cells was closely related to short progression free survival time; however, it was not correlated with other clinicopathological factors. Intracellular expression of TIMD4 was observed in the RCC cell line, 786-O. In vitro studies using 786-O cells and shRNA targeting TIMD4 indicated that TIMD4 expression was associated with resistance to sorafenib but not with cell proliferation. TIMD4 might be useful as a prognostic factor and may also be a new target for therapy of ccRCC.

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The role and mechanism of autophagy in sorafenib targeted cancer therapy

Cited by 29 publications

References 23 publications

Inhibition of autophagy enhances the targeted therapeutic effect of sorafenib in thyroid cancer

Inhibition of autophagy enhances the targeted therapeutic effect of sorafenib in thyroid cancer

New knowledge of the mechanisms of sorafenib resistance in liver cancer

The significance of TIMD4 expression in clear cell renal cell carcinoma

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