Altered molecular pathways decides the treatment outcome of Hsp90 inhibitors against breast cancer cells

Vykuntham, Naga Gowthami; Suran, Sourabh; Siripini, Satish; John, Samu; Kumar, Pankaj; Paithankar, Khanderao; Subbarao, Sreedhar Amere

doi:10.1016/j.tiv.2020.104828

Cited by 8 publications

(2 citation statements)

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“…Some studies indicate that therapeutic stimulation of metastatic/drug‐resistant cells stimulates the endogenous population of cancer stem cells or stimulates cancer cells to behave like cancer stem‐like cells. Earlier, we showed that metastatic breast cancer cells in response to 17AAG treatment exhibit incomplete epithelial to mesenchymal transition, thus exhibit inappropriate cell phenotypes, leading to altered homing properties 44 . Therefore, we hypothesize that the inability of cancer cells to exhibit stem‐like characteristics, may sensitize them to 17AAG treatment and metastasis inhibition.…”

Section: Discussionmentioning

confidence: 88%

“…Earlier, we showed that metastatic breast cancer cells in response to 17AAG treatment exhibit incomplete epithelial to mesenchymal transition, thus exhibit inappropriate cell phenotypes, leading to altered homing properties. 44 Therefore, we hypothesize that the inability of cancer cells to exhibit stem‐like characteristics, may sensitize them to 17AAG treatment and metastasis inhibition. In the present, strengthening our hypothesis, we observed indistinct ratios of CD44 and CD24, being unable to drive cellular differentiation (incomplete EMT).…”

Section: Discussionmentioning

confidence: 99%

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The matrix metalloproteinase 7 (MMP7) links Hsp90 chaperone with acquired drug resistance and tumor metastasis

Kumar

Siripini²,

Sreedhar

2020

Cancer Reports

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Background: Cancer emergence is associated with a series of cellular transformations that include acquired drug resistance followed by tumor metastasis. Matrix metalloproteinases (MMPs) and Hsp90 chaperone are implicated in tumor progression, however, they are not studied in the context of drug resistance. Aims: In the present study, we aimed at understanding the cross-talk between acquired drug resistance and tumor progression, linking MMP7 and Hsp90. Methods and results: We have developed an in vitro model system for acquired drug resistance and studied the correlation between MMP7 and Hsp90. We demonstrate that enhanced drug efflux activity correlates with the induced expression and activity of MMP7, and enhanced metastatic potential of cells, however, in Hsp90-dependent manner. The MMP7 overexpression alone could enhance the drug efflux activity marginally, and metastasis significantly. However, challenging these cells with 17AAG has significantly increased the drug efflux activity and, in contrast, decreased the metastatic potential. Evaluating our in vitro findings in mice xenografts revealed that MMP7 overexpression facilitates altered homing properties. However, these cells, in response to 17AAG treatment, exhibited increased localized tumor growth but decreased tumor metastasis. Conclusion: We demonstrated a cross-talk between Hsp90 and MMP7 in regulating the acquired drug resistance and tumor progression. Our findings provide novel insights on targeting drug resistant-tumors.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%