Protective autophagy promotes the resistance of HER2-positive breast cancer cells to lapatinib

Chen, Suning; Zhu, Xulong; Qiao, Hongyu; Ye, Mingxiang; Lai, Xiaofeng; Yu, Shentong; Ding, Likun; Wen, Aidong; Zhang, Jian

doi:10.1007/s13277-015-3800-9

Cited by 36 publications

(37 citation statements)

References 32 publications

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“…The double sided functions of autophagy implicate its paradoxical roles in anticancer treatments, increasing or diminishing their anticancer activity. However, an increasing amount of evidence suggests that autophagy׳s pro-survival function plays a significant role in chemoresistance in a many different cancer types33, 34, 35, 36, 37, 38.…”

Section: Mechanisms Of Multidrug Resistancementioning

confidence: 99%

Regulation of multidrug resistance by microRNAs in anti-cancer therapy

An¹,

Sarmiento

Tan

et al. 2017

Acta Pharmaceutica Sinica B

162

132

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Multidrug resistance (MDR) remains a major clinical obstacle to successful cancer treatment. Although diverse mechanisms of MDR have been well elucidated, such as dysregulation of drugs transporters, defects of apoptosis and autophagy machinery, alterations of drug metabolism and drug targets, disrupti on of redox homeostasis, the exact mechanisms of MDR in a specific cancer patient and the cross-talk among these different mechanisms and how they are regulated are poorly understood. MicroRNAs (miRNAs) are a new class of small noncoding RNAs that could control the global activity of the cell by post-transcriptionally regulating a large variety of target genes and proteins expression. Accumulating evidence shows that miRNAs play a key regulatory role in MDR through modulating various drug resistant mechanisms mentioned above, thereby holding much promise for developing novel and more effective individualized therapies for cancer treatment. This review summarizes the various MDR mechanisms and mainly focuses on the role of miRNAs in regulating MDR in cancer treatment.

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Section: Mechanisms Of Multidrug Resistancementioning

confidence: 99%

Regulation of multidrug resistance by microRNAs in anti-cancer therapy

An¹,

Sarmiento

Tan

et al. 2017

Acta Pharmaceutica Sinica B

162

132

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“…Many strategies to overcome drug resistance in cancer have been studied. For example, Wang et al (8) have previously reported that HMGB1-mediated autophagy promotes neuroblastoma cell chemoresistance; protective autophagy has been demonstrated to promote lapatinib resistance in HER2-positive breast cancer cells (9); Giuliano et al (10) have demonstrated that inhibition of autophagy leads to sunitinib resistance in renal clear cell carcinoma; and in a study conducted by Crystal et al (11), MEK activation was revealed to promote ceritinib resistance and MEK inhibitor treatment was able to reverse resistance to ceritinib. A recent study indicated that caveolin-1 (CAV-1) was highly expressed in cancer stem cells and decreased cells' chemosensitivity (12).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of caveolin-1 reduces Taxol resistance in human osteosarcoma cells by attenuating PI3K-Akt-JNK dependent autophagy

Guan

Yuan

et al. 2016

Experimental and Therapeutic Medicine

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Caveolin-1 (CAV-1), which is an oncoprotein and a tumor suppressor, is highly expressed in normal osteoblasts. Although researchers have investigated its role in human osteosarcoma, the mechanism of caveolin-1 action in osteosarcoma remains unknown. In the present study, Saos-2 and U-2 OS cells were cultured with a continuous induction protocol of gradually increasing Taxol concentration for 6 months to establish drug-resistant cell lines. CAV-1 expression levels in osteosarcoma cells were detected via western blotting and quantitative polymerase chain reaction. CAV-1 knockdown was achieved using a short hair-pin RNA lentivirus vector, and cell viability was analyzed by MTT assay. The effect of caveolin-1 on autophagy was investigated, and the downregulation of caveolin-1 and increased autophagy was identified in Taxol-resistant osteosarcoma cells. In addition, the results of the present study demonstrated that downregulation of caveolin-1 promotes autophagy and induces osteosarcoma cell resistance to Taxol. Notably, overexpression of CAV-1 resensitized drug-resistant cells to Taxol via declined autophagy. In conclusion, CAV-1 was demonstrated to be downregulated in Taxol-resistant osteosarcoma cells, and overexpression of CAV-1 in human osteosarcoma cells suppressed Taxol resistance by attenuating PI3K-Akt-JNK-dependent autophagy. The present findings suggest that further investigation into CAV-1's role in Taxol resistance is warranted. In the future, detection of CAV-1 may be used as an indicator to evaluate the treatment and prognosis of patients with osteosarcoma.

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“…In response to these observations, several clinical trials are currently aimed at assessing the effect of pharmacologic inhibition of autophagy in order to determine if inhibiting this process improves the efficacy of chemotherapeutic agents [37]. Because HER2 + /ErbB2 + breast cancer cells that have become resistant to HER2/ErbB2 inhibitors exhibit higher levels of basal autophagy [39, 41, 42], it is proposed that Hunk upregulates autophagy in HER2 + /ErbB2 + breast cancer cells as a survival mechanism, thus promoting the acquisition of drug resistance to HER2/ErbB2 inhibitors. Therefore, targeting Hunk has the potential to improve the treatment of drug resistant HER2 + /ErbB2 + breast cancers through downregulation of autophagy.…”

Section: Hunk Is Implicated In Her2+/erbb2+ Breast Cancer and Devementioning

confidence: 99%

Hormonally up-regulated neu-associated kinase: A novel target for breast cancer progression

Zambrano

Neely

Yeh

2017

Pharmacological Research

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Hormonally Up-regulated Neu-associated Kinase (Hunk) is a protein kinase that was originally identified in the murine mammary gland and has been shown to be highly expressed in Human Epidermal Growth Factor Receptor 2 positive (HER2+/ErbB2+) breast cancer cell lines as well as MMTV-neu derived mammary tumor cell lines. However, the physiological role of Hunk has been largely elusive since its identification. Though Hunk is predicted to be a Serine/Threonine (Ser/Thr) protein kinase with homology to the SNF1/AMPK family of protein kinases, there are no known Hunk substrates that have been identified to date. Recent work demonstrates a role for Hunk in HER2+/ErbB2+ breast cancer progression, including drug resistance to HER2/ErbB2 inhibitors, with Hunk potentially acting downstream of HER2/ErbB2 and the PI3K/Akt pathway. These studies have collectively shown that Hunk plays a vital role in promoting mammary tumorigenesis, as Hunk knockdown via shRNA in xenograft tumor models or crossing MMTV-neu or Pten-deficient genetically engineered mouse models into a Hunk knockout (Hunk−/−) background impairs mammary tumor growth in vivo. Because the majority of HER2+/ErbB2+ breast cancer patients acquire drug resistance to HER2/ErbB2 inhibitors, the characterization of novel drug targets like Hunk that have the potential to simultaneously suppress tumorigenesis and potentially enhance efficacy of current therapeutics is an important facet of drug development. Therefore, work aimed at uncovering specific regulatory functions for Hunk that could contribute to this protein kinase’s role in both tumorigenesis and drug resistance will be informative. This review focuses on what is currently known about this under-studied protein kinase, and how targeting Hunk may prove to be a potential therapeutic target for the treatment of breast cancer.

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Protective autophagy promotes the resistance of HER2-positive breast cancer cells to lapatinib

Cited by 36 publications

References 32 publications

Regulation of multidrug resistance by microRNAs in anti-cancer therapy

Regulation of multidrug resistance by microRNAs in anti-cancer therapy

Overexpression of caveolin-1 reduces Taxol resistance in human osteosarcoma cells by attenuating PI3K-Akt-JNK dependent autophagy

Hormonally up-regulated neu-associated kinase: A novel target for breast cancer progression

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